Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor!
|
|
|
- Avice Lester
- 6 years ago
- Views:
Transcription
1 Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor Allosteric pocket SHP2 Phosphatase ovel allosteric Phosphatase inhibitor Evan Carder Wipf Group Current Literature August 06, 2016 [1]. J. Med. Chem., Article ASAP [2] ature 2016, 535, 148.
2 Regulation of Cell Signaling Protein Kinase +ATP P Protein Phosphatase -PO4-3 Protein Kinase ca. 518 protein kinases Catalyze the phosphorylation Control the amplitude of the response Receptor and on-receptor kinases Serine/Threonine and Tyrosine Protein Phosphatase ca. 107 protein phosphatases Catalyze de-phosphorylation Control the rate and duration of the response Receptor and on-receptor kinases assical tyrosine-specific PTPs (37 genes) Dual specificity phosphatases (65 genes) [1]. Drug Discovery Today 2016, 21, 1.. [2]. at. Rev. 2006, 7, /06/16 Evan Wipf Group 2
3 SHP2 Structure SH2 Domain on-transmembrane, cytoplasmic protein tyrosine phosphatase (PTP) SH2 Domain PTP domain Enzymatic region responsible for catalyzing de-phosphorylation Src-homology-2 domains (SH2) Tandem SH2 domains Bind to phosphorylated tyrosine residues Regulatory domains Flank the catalytic domain (PTP domain) Regulate enzymatic activity PTP Domain [1].Histol. Histopathol. 2007, 22, /06/16 Evan Wipf Group 3
4 SHP2 Cell Signaling Receptor Tyrosine Kinase (RTK) Extracellular Intracellular SHP2 PI3K Gab1 Ras Akt F-κB ERK Cell proliferation, differentiation, apoptosis, and survival [1]. ature 2016, 535, 148. [2]. Histol. Histopathol. 2007, 22, [3]. at. Rev. 2006, 7, /06/16 Evan Wipf Group 4
5 Design of Phosphatase Inhibitors - O O P O - O substrate Phosphorylated Tyrosine SHP2 Inhibitors possessing ionizable functional groups Ph O H H O H O O S Oa OH O S O Oa HO 2 C HO 2 C H H O HO HO O H O AT IC 50 (SHP2): 2.5 um SC IC 50 (SHP2): 0.3 um IC 50 (SHP2): 0.8 um IlB08 IC 50 (SHP2): 5.5 um 08/06/16 Evan Wipf Group 5
6 Allosteric Modulators Orthosteric binding site a distinct binding site for a protein s endogenous ligand Allosteric binding site a site that is topologically and functionally distinct to the orthosteric binding site. Orthosteric site Allosteric site Endogenous Ligand Allosteric modulators: regulation of protein activity by binding of an effector molecule at a site other than the protein s orthosteric site. Mechanism: Allosteric modulators traditional impact protein activity by inducing conformational change that can either enhance or reduce protein activity Significance: Greater selectivity may be obtained by targeting allosteric sites including subtype selectivity within receptor families. Also, allosteric modulators can have improved physiochemical and drug metabolism/pharmacokinetic properties [1]. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 165. [2]. Med. Princ. Pract. 2013, 22, 418. [3] at. Biotech. 2014, 22, /06/16 Evan Wipf Group 6
7 Central hypothesis. Targeted inhibition of SHP2 leads to RTK-dependent cancer reduction. Aim 1. Development of an allosteric SHP2 small molecule inhibitor Subaim 1.1. Identify allosteric small molecule inhibitor Subaim 1.2. Optimize Hit by SAR and SBDD Subaim 1.3. Biologically evaluate SHP2 inhibitor 08/06/16 Evan Wipf Group 7
8 Identification of an allosteric SHP2 small molecule inhibitor 100,000 Compounds Library Screen ature 2016, 535, /06/16 Full Length SHP2 PTP Domain Evan Wipf Group 8
9 Hit H 2 H SHP836 Allosteric Modulator SHP2 IC 50 = 12 um 08/06/16 Evan Wipf Group 9
10 SHP836 Chemical Analysis Intermolecular Interactions Ion-dipole and dipole-dipole interactions Hydrophobic Pi interactions HBD or HBA Ionic Ionic or electrostatic bonds Pi interactions Hydrophobic interactions Hydrogen bonds Halogen bonding Halogen bond Hydrophobic Pi interactions H 2 HBA HBA H Hydrophobic Hydrophobic HBD or HBA Ionic [1]. J. Med. Chem. 2010, 53, /06/16 Evan Wipf Group 10
11 SHP836 & SHP2 Co-crystal Structure SH2 Domain SH2 Domain PTP Domain 08/06/16 Evan Wipf Group PDB: 2SHP 11
12 SHP836 & SHP2 Co-crystal Structure: Key Intermolecular Interactions Protein-Ligand Interactions -H2 form H-bonding with Glu250 backbone P491 E250 E249 L254 Q495 Methyl groups form van der Waals interactions with His114 and Glu249 The dichlorophenyl ring resides in a hydrophobic pocket (Leu254, Gln257, Pro491) water H114 R111 PDB: 2SHP 08/06/16 L216 Cationic-Pi interaction with dihlorophenyl ring and Arg111 H-bonding network with water molecules Evan Wipf Group 12
13 Optimization by SAR and SBDD Zone 1 Zone 2 H 2 Zone 3 H Br H 2 Ar-B(OH) 2 Pd 2 (dppf), K 3 PO 4 MeC, H 2 O, 120 o C Ar H 2 amine K 3 PO 4, MP, 140 o C Ar H 2 H 08/06/16 Evan Wipf Group 13
14 Zone 1 Zone 1 Zone 2 H 2 Zone 3 H 08/06/16 Evan Wipf Group 14
15 Zone 3 Zone 1 Zone 2 H 2 Zone 3 H 08/06/16 Evan Wipf Group 15
16 Zone 2 Zone 1 Zone 2 H 2 Zone 3 H 2 08/06/16 Evan Wipf Group 16
17 Improvement H 2 H 2 H SHP836 SHP2 Allosteric Modulator SHP2 IC 50 = 12 um SHP099 SHP2 Allosteric Modulator SHP2 IC 50 = 0.07 um H 2 08/06/16 Evan Wipf Group 17
18 SHP099 & SHP2 Co-crystal Structure: Key Intermolecular Interactions Protein-Ligand Interactions Conserved -H2 H-bonding with Glu250 backbone ew H-bond between pyrazine and Arg111 sidechain Dichlorophenyl resides in a hydrophobic pocket (Leu254, Gln257, Pro491) Cationic-Pi interaction with dichlorophenyl ring Arg111 PDB: 5EHR ature 2016, 535, 148. ew H-bonding between piperidine amine and F113 backbone 08/06/16 Evan Wipf Group 18
19 Biological Selectivity ature 2016, 535, /06/16 Evan Wipf Group 19
20 In-Vivo Characterization of SHP099 in EGFR-Amplified KYSE-520 Cells Receptor Tyrosine Kinase (RTK) Extracellular Intracellular SHP2 PI3K Gab1 Ras Akt F-κB ERK Cell proliferation, differentiation, apoptosis, and survival ature 2016, 535, /06/16 Evan Wipf Group 20
21 Conclusion H 2 H 2 SHP099 SHP2 Allosteric Modulator SHP2 IC 50 = 0.07 um Identified an allosteric site that is influential in the enzymatic activity of SHP2, providing a platform for future drug discovery efforts. Developed a potent allosteric modulator of SHP2 that exhibits selectivity over other protein phosphatases. Pharmacological inhibition of SHP2 demonstrates a novel therapeutic approach to target RTK-dependent cancers. 08/06/16 Evan Wipf Group 21
Molecular Cell Biology - Problem Drill 19: Cell Signaling Pathways and Gene Expression
Molecular Cell Biology - Problem Drill 19: Cell Signaling Pathways and Gene Expression Question No. 1 of 10 1. Which statement about cell signaling is correct? Question #1 (A) Cell signaling involves receiving
Previous Class. Today. Detection of enzymatic intermediates: Protein tyrosine phosphatase mechanism. Protein Kinase Catalytic Properties
Previous Class Detection of enzymatic intermediates: Protein tyrosine phosphatase mechanism Today Protein Kinase Catalytic Properties Protein Phosphorylation Phosphorylation: key protein modification
G-Protein Signaling. Introduction to intracellular signaling. Dr. SARRAY Sameh, Ph.D
G-Protein Signaling Introduction to intracellular signaling Dr. SARRAY Sameh, Ph.D Cell signaling Cells communicate via extracellular signaling molecules (Hormones, growth factors and neurotransmitters
Enzymes Part III: regulation II. Dr. Mamoun Ahram Summer, 2017
Enzymes Part III: regulation II Dr. Mamoun Ahram Summer, 2017 Advantage This is a major mechanism for rapid and transient regulation of enzyme activity. A most common mechanism is enzyme phosphorylation
Receptor mediated Signal Transduction
Receptor mediated Signal Transduction G-protein-linked receptors adenylyl cyclase camp PKA Organization of receptor protein-tyrosine kinases From G.M. Cooper, The Cell. A molecular approach, 2004, third
Protein kinases are enzymes that add a phosphate group to proteins according to the. ATP + protein OH > Protein OPO 3 + ADP
Protein kinase Protein kinases are enzymes that add a phosphate group to proteins according to the following equation: 2 ATP + protein OH > Protein OPO 3 + ADP ATP represents adenosine trisphosphate, ADP
Life History of A Drug
DRUG ACTION & PHARMACODYNAMIC M. Imad Damaj, Ph.D. Associate Professor Pharmacology and Toxicology Smith 652B, 828-1676, mdamaj@hsc.vcu.edu Life History of A Drug Non-Specific Mechanims Drug-Receptor Interaction
Chapter 11: Enzyme Catalysis
Chapter 11: Enzyme Catalysis Matching A) high B) deprotonated C) protonated D) least resistance E) motion F) rate-determining G) leaving group H) short peptides I) amino acid J) low K) coenzymes L) concerted
Signaling. Dr. Sujata Persad Katz Group Centre for Pharmacy & Health research
Signaling Dr. Sujata Persad 3-020 Katz Group Centre for Pharmacy & Health research E-mail:sujata.persad@ualberta.ca 1 Growth Factor Receptors and Other Signaling Pathways What we will cover today: How
Tyrosine kinases. Cell surface receptors ligand binding. Producer cell RNA. Target cell
Tyrosine kinases http://msbl.helsinki.fi/tkseminar roducer cell Signaling molecules Receptor binding Signal transduction Target cell Activation of Gene expression RNA Biological responses proliferation,
Cell Signaling part 2
15 Cell Signaling part 2 Functions of Cell Surface Receptors Other cell surface receptors are directly linked to intracellular enzymes. The largest family of these is the receptor protein tyrosine kinases,
Chapter 15: Signal transduction
Chapter 15: Signal transduction Know the terminology: Enzyme-linked receptor, G-protein linked receptor, nuclear hormone receptor, G-protein, adaptor protein, scaffolding protein, SH2 domain, MAPK, Ras,
Synthesis and Biological Evaluation of Protein Kinase D Inhibitors
Synthesis and Biological Evaluation of Protein Kinase D Inhibitors Celeste Alverez Topic Seminar October 26, 2013 Celeste Alverez @ Wipf Group 10/26/2013 1 Protein Kinase D (PKD) A novel family of serine/threonine
Propagation of the Signal
OpenStax-CNX module: m44452 1 Propagation of the Signal OpenStax College This work is produced by OpenStax-CNX and licensed under the Creative Commons Attribution License 3.0 By the end of this section,
Patrick, An Introduction to Medicinal Chemistry 4e Chapter 5 Receptors and signal transduction
atrick, An Introduction to Medicinal Chemistry 4e Answers to end-of-chapter questions 1) The diagram in the question shows two important hydrogen bonding interactions where AT acts both as a hydrogen bond
The elements of G protein-coupled receptor systems
The elements of G protein-coupled receptor systems Prostaglandines Sphingosine 1-phosphate a receptor that contains 7 membrane-spanning domains a coupled trimeric G protein which functions as a switch
Bio 111 Study Guide Chapter 11 Cell Communication
Bio 111 Study Guide Chapter 11 Cell Communication BEFORE CLASS: Reading: Read the introduction on p. 210, and for Concept 11.1, read from the first full paragraph on p. 212. Read all of Concept 11.2. Pay
P450 CYCLE. All P450s follow the same catalytic cycle of;
P450 CYCLE All P450s follow the same catalytic cycle of; 1. Initial substrate binding 2. First electron reduction 3. Oxygen binding 4. Second electron transfer 5 and 6. Proton transfer/dioxygen cleavage
Regulation of cell function by intracellular signaling
Regulation of cell function by intracellular signaling Objectives: Regulation principle Allosteric and covalent mechanisms, Popular second messengers, Protein kinases, Kinase cascade and interaction. regulation
Enzyme-coupled Receptors. Cell-surface receptors 1. Ion-channel-coupled receptors 2. G-protein-coupled receptors 3. Enzyme-coupled receptors
Enzyme-coupled Receptors Cell-surface receptors 1. Ion-channel-coupled receptors 2. G-protein-coupled receptors 3. Enzyme-coupled receptors Cell-surface receptors allow a flow of ions across the plasma
Vets 111/Biov 111 Cell Signalling-2. Secondary messengers the cyclic AMP intracellular signalling system
Vets 111/Biov 111 Cell Signalling-2 Secondary messengers the cyclic AMP intracellular signalling system The classical secondary messenger model of intracellular signalling A cell surface receptor binds
Signaling Through Immune System Receptors (Ch. 7)
Signaling Through Immune System Receptors (Ch. 7) 1. General principles of signal transduction and propagation. 2. Antigen receptor signaling and lymphocyte activation. 3. Other receptors and signaling
Targeting PPIs in Oncology using a Fragment-Based Drug Discovery Approach Justin F. Bower CRUK Beatson Institute
Targeting PPIs in Oncology using a Fragment-Based Drug Discovery Approach Justin F. Bower CRUK Beatson Institute Cancer Research UK Beatson Institute Establish an outstanding basic research programme into
This exam consists of two parts. Part I is multiple choice. Each of these 25 questions is worth 2 points.
MBB 407/511 Molecular Biology and Biochemistry First Examination - October 1, 2002 Name Social Security Number This exam consists of two parts. Part I is multiple choice. Each of these 25 questions is
The Tissue Engineer s Toolkit
The Tissue Engineer s Toolkit Stimuli Detection and Response Ken Webb, Ph. D. Assistant Professor Dept. of Bioengineering Clemson University Environmental Stimulus-Cellular Response Environmental Stimuli
Concise Reference. HER2 Testing in Breast Cancer. Mary Falzon, Angelica Fasolo, Michael Gandy, Luca Gianni & Stefania Zambelli
Concise Reference Testing in Breast Cancer Mary Falzon, Angelica Fasolo, Michael Gandy, Luca Gianni & Stefania Zambelli Extracted from Handbook of -Targeted Agents in Breast Cancer ublished by Springer
Biochem 503 Fall Protein Tyr Phosphatases
Biochem 503 Fall 2005 Protein Tyr Phosphatases David Brautigan assigned reading: Stoker (2005) J. Endocrin. 185:19-33 History 1981-1982 First description of P-Tyr specific phosphohydrolyase activity in
Lecture 5: Drug targets (continued)
Lecture 5: Drug targets (continued) IIa. Enzymes as drug targets (HMG-CoA example) Many drugs are inhibitors of enzymes that catalyze biologically important reactions. The conversion of HMG-CoA to mevalonic
Research Topic Seminar
Research Topic Seminar Dr. Claire Coleman The Chemistry and Biology of Wortmannin Claire Coleman @ Wipf Group 1 3/13/2004 ff white to pale yellow solid Hygroscopic/Light sensitive Small molecule natural
1. Arresting cancer by energy starvation
1. Arresting cancer by energy starvation Cancer, a top killer, may be stopped from its deadly progression with the latest discovery by NUS researchers. They have found how a compound that is undergoing
Lecture 15. Signal Transduction Pathways - Introduction
Lecture 15 Signal Transduction Pathways - Introduction So far.. Regulation of mrna synthesis Regulation of rrna synthesis Regulation of trna & 5S rrna synthesis Regulation of gene expression by signals
Phenylketonuria (PKU) Structure of Phenylalanine Hydroxylase. Biol 405 Molecular Medicine
Phenylketonuria (PKU) Structure of Phenylalanine Hydroxylase Biol 405 Molecular Medicine 1998 Crystal structure of phenylalanine hydroxylase solved. The polypeptide consists of three regions: Regulatory
Tala Saleh. Ahmad Attari. Mamoun Ahram
23 Tala Saleh Ahmad Attari Minna Mushtaha Mamoun Ahram In the previous lecture, we discussed the mechanisms of regulating enzymes through inhibitors. Now, we will start this lecture by discussing regulation
Properties of amino acids in proteins
Properties of amino acids in proteins one of the primary roles of DNA (but far from the only one!!!) is to code for proteins A typical bacterium builds thousands types of proteins, all from ~20 amino acids
KEY CONCEPT QUESTIONS IN SIGNAL TRANSDUCTION
Signal Transduction - Part 2 Key Concepts - Receptor tyrosine kinases control cell metabolism and proliferation Growth factor signaling through Ras Mutated cell signaling genes in cancer cells are called
Lipids and Membranes
Lipids and Membranes Presented by Dr. Mohammad Saadeh The requirements for the Pharmaceutical Biochemistry I Philadelphia University Faculty of pharmacy Membrane transport D. Endocytosis and Exocytosis
Basics of Signal Transduction. Ebaa M Alzayadneh, PhD
Basics of Signal Transduction Ebaa M Alzayadneh, PhD What is signal transduction? Cell signaling The science of understanding how individual cells sense their environments and respond to stimuli... how
Chapter 10. Regulatory Strategy
Chapter 10 Regulatory Strategy Regulation of enzymatic activity: 1. Allosteric Control. Allosteric proteins have a regulatory site(s) and multiple functional sites Activity of proteins is regulated by
Principles of Genetics and Molecular Biology
Cell signaling Dr. Diala Abu-Hassan, DDS, PhD School of Medicine Dr.abuhassand@gmail.com Principles of Genetics and Molecular Biology www.cs.montana.edu Modes of cell signaling Direct interaction of a
INTERACTION DRUG BODY
INTERACTION DRUG BODY What the drug does to the body What the body does to the drug Receptors - intracellular receptors - membrane receptors - Channel receptors - G protein-coupled receptors - Tyrosine-kinase
Function. BRAF (gene) From Wikipedia, the free encyclopedia
BRAF (gene) From Wikipedia, the free encyclopedia BRAF is a human gene that makes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-raf murine sarcoma viral oncogene homolog
PHRM20001 NOTES PART 1 Lecture 1 History of Pharmacology- Key Principles
PHRM20001 NOTES PART 1 Lecture 1 History of Pharmacology- Key Principles Hippocrates (5 th century BCE):... benefit my patients according to my greatest ability and judgment, and I will do no harm or injustice
Cellular Signaling Pathways. Signaling Overview
Cellular Signaling Pathways Signaling Overview Signaling steps Synthesis and release of signaling molecules (ligands) by the signaling cell. Transport of the signal to the target cell Detection of the
CHAPTER 21: Amino Acids, Proteins, & Enzymes. General, Organic, & Biological Chemistry Janice Gorzynski Smith
CHAPTER 21: Amino Acids, Proteins, & Enzymes General, Organic, & Biological Chemistry Janice Gorzynski Smith CHAPTER 21: Amino Acids, Proteins, Enzymes Learning Objectives: q The 20 common, naturally occurring
The PI3K/AKT axis. Dr. Lucio Crinò Medical Oncology Division Azienda Ospedaliera-Perugia. Introduction
The PI3K/AKT axis Dr. Lucio Crinò Medical Oncology Division Azienda Ospedaliera-Perugia Introduction Phosphoinositide 3-kinase (PI3K) pathway are a family of lipid kinases discovered in 1980s. They have
Excerpt from J. Mol. Biol. (2002) 320, :
Excerpt from J. Mol. Biol. (2002) 320, 1095 1108: Crystal Structure of the Ternary Complex of the Catalytic Domain of Human Phenylalanine Hydroxylase with Tetrahydrobiopterin and 3-(2-Thienyl)-L-alanine,
Signal Transduction I
Signal Transduction I Prof. Tianhua Zhou Department of Cell Biology Zhejiang University School of Medicine Office hours by appointment tzhou@zju.edu.cn Signal transduction: Key contents for signal transduction:
Lecture: CHAPTER 13 Signal Transduction Pathways
Lecture: 10 17 2016 CHAPTER 13 Signal Transduction Pathways Chapter 13 Outline Signal transduction cascades have many components in common: 1. Release of a primary message as a response to a physiological
CHAPTER 10: REGULATORY STRATEGIES. Traffic signals control the flow of traffic
CHAPTER 10: REGULATORY STRATEGIES Traffic signals control the flow of traffic INTRODUCTION CHAPTER 10 The activity of enzymes must often be regulated so that they function at the proper time and place.
Cell Communication. Cell Communication. Communication between cells requires: ligand: the signaling molecule
Cell Communication Cell Communication Communication between cells requires: ligand: the signaling molecule receptor protein: the molecule to which the ligand binds (may be on the plasma membrane or within
Fundamentals of Pharmacology
Fundamentals of Pharmacology Topic Page Receptors 2 Ion channels / GABA 4 GPCR s 6 TK receptors 8 Basics of PK 11 ADR s / Clinical study design 13 Introduction to the ANS 16 Cholinergic Pharmacology 20
Chemical Nature of the Amino Acids. Table of a-amino Acids Found in Proteins
Chemical Nature of the Amino Acids All peptides and polypeptides are polymers of alpha-amino acids. There are 20 a- amino acids that are relevant to the make-up of mammalian proteins (see below). Several
Pharmacologic Principles. Dr. Alia Shatanawi
Pharmacologic Principles Dr. Alia Shatanawi Definitions Drug: It is any chemical that affect living processes. It modifies an already existing function, and does not create a new function. 2 What is Pharmacology?
Signal Transduction Cascades
Signal Transduction Cascades Contents of this page: Kinases & phosphatases Protein Kinase A (camp-dependent protein kinase) G-protein signal cascade Structure of G-proteins Small GTP-binding proteins,
MHC Class II. Alexandra López Laura Taberner Gemma Vilajosana Ilia Villate. Structural Biology Academic year Universitat Pompeu Fabra
MHC Class II Alexandra López Laura Taberner Gemma Vilajosana Ilia Villate Structural Biology Academic year 2012-2013 Universitat Pompeu Fabra Index - Introduction - Peptide binding to MHC class II - pockets
Molecular Medicine: Gleevec and Chronic Myelogenous Leukemia. Dec 14 & 19, 2006 Prof. Erin O Shea Prof. Dan Kahne
Molecular Medicine: Gleevec and Chronic Myelogenous Leukemia Dec 14 & 19, 2006 Prof. Erin Shea Prof. Dan Kahne 1 Cancer, Kinases and Gleevec: 1. What is CML? a. Blood cell maturation b. Philadelphia Chromosome
Chapter 11. Cell Communication. Signal Transduction Pathways
Chapter 11 Cell Communication Signal Transduction Pathways Signal-Transduction Pathway Signal on a cell s surface is converted into a specific cellular response Local signaling (short distance) - Paracrine
Biological systems interact, and these systems and their interactions possess complex properties. STOP at enduring understanding 4A
Biological systems interact, and these systems and their interactions possess complex properties. STOP at enduring understanding 4A Homework Watch the Bozeman video called, Biological Molecules Objective:
Maha AbuAjamieh. Tamara Wahbeh. Mamoon Ahram
12 Maha AbuAjamieh Tamara Wahbeh Mamoon Ahram - - Go to this sheet s last page for definitions of the words with an asterisk above them (*) - You should memorise the 3-letter abbreviations, of all the
Proteins are sometimes only produced in one cell type or cell compartment (brain has 15,000 expressed proteins, gut has 2,000).
Lecture 2: Principles of Protein Structure: Amino Acids Why study proteins? Proteins underpin every aspect of biological activity and therefore are targets for drug design and medicinal therapy, and in
INTERACTION DRUG BODY
INTERACTION DRUG BODY What the drug does to the body What the body does to the drug Receptors - intracellular receptors - membrane receptors - Channel receptors - G protein-coupled receptors - Tyrosine-kinase
WHY TARGETTING SIGNALLING PATHWAYS?
WHY TARGETTING SIGNALLING PATHWAYS? Cancer cells are particularly sensitive to stress therefore sensitive to inhibition of their hyper activated signaling proteins the re instatement of lost tumor suppressors.
Biol220 Cell Signalling Cyclic AMP the classical secondary messenger
Biol220 Cell Signalling Cyclic AMP the classical secondary messenger The classical secondary messenger model of intracellular signalling A cell surface receptor binds the signal molecule (the primary
Chapter 3: Amino Acids and Peptides
Chapter 3: Amino Acids and Peptides BINF 6101/8101, Spring 2018 Outline 1. Overall amino acid structure 2. Amino acid stereochemistry 3. Amino acid sidechain structure & classification 4. Non-standard
PROTEINS. Amino acids are the building blocks of proteins. Acid L-form * * Lecture 6 Macromolecules #2 O = N -C -C-O.
Proteins: Linear polymers of amino acids workhorses of the cell tools, machines & scaffolds Lecture 6 Macromolecules #2 PRTEINS 1 Enzymes catalysts that mediate reactions, increase reaction rate Structural
Principles of cell signaling Lecture 4
Principles of cell signaling Lecture 4 Johan Lennartsson Molecular Cell Biology (1BG320), 2014 Johan.Lennartsson@licr.uu.se 1 Receptor tyrosine kinase-induced signal transduction Erk MAP kinase pathway
Biol403 MAP kinase signalling
Biol403 MAP kinase signalling The mitogen activated protein kinase (MAPK) pathway is a signalling cascade activated by a diverse range of effectors. The cascade regulates many cellular activities including
Objective: You will be able to explain how the subcomponents of
Objective: You will be able to explain how the subcomponents of nucleic acids determine the properties of that polymer. Do Now: Read the first two paragraphs from enduring understanding 4.A Essential knowledge:
Lab Results: 1. Document the initial and final egg masses. 2. Calculate the percent change
Lab Results: 1. Document the initial and final egg masses. 2. Calculate the percent change 3. Draw an arrow showing which way water traveled (in or out of the egg) on your post lab. CHI- SQUARE: What if
Signal Transduction Pathways. Part 2
Signal Transduction Pathways Part 2 GPCRs G-protein coupled receptors > 700 GPCRs in humans Mediate responses to senses taste, smell, sight ~ 1000 GPCRs mediate sense of smell in mouse Half of all known
Properties of Allosteric Enzymes
Properties of Allosteric Enzymes (1) An allosteric enzyme possesses at least spatially distinct binding sites on the protein molecules the active or the catalytic site and the regulator or the allosteric
Discovery and Optimization of Inhibitors of STAT3 Activation for the Treatment of Squamous Cell Carcinoma of the Head and Neck
Discovery and ptimization of Inhibitors of STAT3 Activation for the Treatment of Squamous Cell Carcinoma of the Head and Neck Feng Zhang Wipf Group Research Topic Seminar 02-09-2013 1 Feng Zhang @ Wipf
Lecture 7: Signaling Through Lymphocyte Receptors
Lecture 7: Signaling Through Lymphocyte Receptors Questions to Consider After recognition of its cognate MHC:peptide, how does the T cell receptor activate immune response genes? What are the structural
Effects of Second Messengers
Effects of Second Messengers Inositol trisphosphate Diacylglycerol Opens Calcium Channels Binding to IP 3 -gated Channel Cooperative binding Activates Protein Kinase C is required Phosphorylation of many
Signal-Transduction Cascades - 2. The Phosphoinositide Cascade
Signal-Transduction Cascades - 2 The Phosphoinositide Cascade Calcium ion as a second messenger Tyrosine kinase and receptor dimerization scribd.com Faisal Khatib JU The Phosphoinositide Cascade Used by
Cellular Physiology (PHSI3009) Contents:
Cellular Physiology (PHSI3009) Contents: Cell membranes and communication 2 nd messenger systems G-coupled protein signalling Calcium signalling Small G-protein signalling o RAS o MAPK o PI3K RHO GTPases
Signal Transduction: G-Protein Coupled Receptors
Signal Transduction: G-Protein Coupled Receptors Federle, M. (2017). Lectures 4-5: Signal Transduction parts 1&2: nuclear receptors and GPCRs. Lecture presented at PHAR 423 Lecture in UIC College of Pharmacy,
Cell cycle, signaling to cell cycle, and molecular basis of oncogenesis
Cell cycle, signaling to cell cycle, and molecular basis of oncogenesis MUDr. Jiří Vachtenheim, CSc. CELL CYCLE - SUMMARY Basic terminology: Cyclins conserved proteins with homologous regions; their cellular
Molecular Biology. general transfer: occurs normally in cells. special transfer: occurs only in the laboratory in specific conditions.
Chapter 9: Proteins Molecular Biology replication general transfer: occurs normally in cells transcription special transfer: occurs only in the laboratory in specific conditions translation unknown transfer:
Identification of GLP1R agonists using a novel high throughput screening assay Wan Namkung, Ph.D.
Identification of GLP1R agonists using a novel high throughput screening assay Wan Namkung, Ph.D. College of Pharmacy, Yonsei University Contents High-throughput screening (HTS) HTS assays for identification
Amino Acids. Lecture 4: Margaret A. Daugherty. Fall Swiss-prot database: How many proteins? From where?
Lecture 4: Amino Acids Margaret A. Daugherty Fall 2004 Swiss-prot database: How many proteins? From where? 1986 Use http://us.expasy.org to get to swiss-prot database Proteins are the workhorses of the
Journal of Advanced Scientific Research
J.Adv.Sci.Res, 2011, 2(1); 01-07 Published on 10 Feb 2011 Review Article Available online through www.sciensage.info Journal of Advanced Scientific Research TYROSINE KINASES: NOVEL TARGETS FOR CANCER THERAPY
Enzymes: The Catalysts of Life
Chapter 6 Enzymes: The Catalysts of Life Lectures by Kathleen Fitzpatrick Simon Fraser University Activation Energy and the Metastable State Many thermodynamically feasible reactions in a cell that could
INTERACTION DRUG BODY
INTERACTION DRUG BODY What the drug does to the body What the body does to the drug Receptors - intracellular receptors - membrane receptors - Channel receptors - G protein-coupled receptors - Tyrosine-kinase
Adenosine triphosphate (ATP)
Adenosine triphosphate (ATP) 1 High energy bonds ATP adenosine triphosphate N NH 2 N -O O P O O P O- O- O O P O- O CH 2 H O H N N adenine phosphoanhydride bonds (~) H OH ribose H OH Phosphoanhydride bonds
Signal Transduction: Information Metabolism. Chem 454: Regulatory Mechanisms in Biochemistry University of Wisconsin-Eau Claire
Signal Transduction: Information Metabolism Chem 454: Regulatory Mechanisms in Biochemistry University of Wisconsin-Eau Claire Introduction Information Metabolism How cells receive, process and respond
Scheme 1. Phosphorylation status of tyrosine residues is controlled by the coordinated action of PTKs and PTPs.
CEM 4170, Medicinal Chemistry University of Missouri Computer Graphics Visualization of roteins and rotein-ligand Complexes Derrick Seiner and Kent S. Gates 1. Introduction. Drugs typically bind to concave
Short polymer. Dehydration removes a water molecule, forming a new bond. Longer polymer (a) Dehydration reaction in the synthesis of a polymer
HO 1 2 3 H HO H Short polymer Dehydration removes a water molecule, forming a new bond Unlinked monomer H 2 O HO 1 2 3 4 H Longer polymer (a) Dehydration reaction in the synthesis of a polymer HO 1 2 3
Chapter 9. Cellular Signaling
Chapter 9 Cellular Signaling Cellular Messaging Page 215 Cells can signal to each other and interpret the signals they receive from other cells and the environment Signals are most often chemicals The
SID#: Also give full SID# (w/ 9) on your computer grid sheet (fill in grids under Student Number) BIO 315 Exam I
SID#: Also give full SID# (w/ 9) on your computer grid sheet (fill in grids under Student Number) BIO 315 Exam I Choose an answer of A,B, C, or D for each of the following Multiple Choice Questions 1-35.
COO - l. H 3 N C a H l R 1
COO - l + H 3 N C a H l R 1 Amino acids There are 20 standard amino acids. All proteins are built from the same amino acids. The most important criteria for classification is affinity to water: hydrophilic
Receptors Families. Assistant Prof. Dr. Najlaa Saadi PhD Pharmacology Faculty of Pharmacy University of Philadelphia
Receptors Families Assistant Prof. Dr. Najlaa Saadi PhD Pharmacology Faculty of Pharmacy University of Philadelphia Receptor Families 1. Ligand-gated ion channels 2. G protein coupled receptors 3. Enzyme-linked
THE HALLMARKS OF CANCER
THE HALLMARKS OF CANCER ONCOGENES - Most of the oncogenes were first identified in retroviruses: EGFR (ErbB), Src, Ras, Myc, PI3K and others (slightly more than 30) - Mutated cellular genes incorporated
2013 W. H. Freeman and Company. 12 Signal Transduction
2013 W. H. Freeman and Company 12 Signal Transduction CHAPTER 12 Signal Transduction Key topics: General features of signal transduction Structure and function of G protein coupled receptors Structure
Molecular Docking Studies on Pyrazolopyrimidine and their Derivatives as Human Phosphoinositide 3-Kinase Inhibitors
Cloud Publications International Journal of Advanced Bioinformatics and Computational Biology 2012, Volume 1, Issue 1, pp. 1-11, Article ID Med-30 Research Article Open Access Molecular Docking Studies
EGFRIndb: Epidermal Growth Factor Receptor Inhibitor database
EGFRIndb: Epidermal Growth Factor Receptor Inhibitor database Inderjit S Yadav 1,3, Harinder Singh 2, Mohd. Imran Khan 1, Ashok Chaudhury 3, G.P.S. Raghava 2 and Subhash M. Agarwal 1 * 1 Bioinformatics
Amino Acids. Review I: Protein Structure. Amino Acids: Structures. Amino Acids (contd.) Rajan Munshi
Review I: Protein Structure Rajan Munshi BBSI @ Pitt 2005 Department of Computational Biology University of Pittsburgh School of Medicine May 24, 2005 Amino Acids Building blocks of proteins 20 amino acids
Structure and Activation of the Visual Pigment Rhodopsin
Seminar 02.12.2011 Structure and Activation of the Visual Pigment Rhodopsin by Steven O.Smith, 2010 Constantin Schneider FB Physik, FU Berlin GPCR: Overview Rhodopsin is a G protein-coupled receptor (GPCR)
Concept 8.3: ATP powers cellular work by coupling exergonic reactions to endergonic reactions
Concept 8.3: ATP powers cellular work by coupling exergonic reactions to endergonic reactions A cell does three main kinds of work: Chemical Transport Mechanical To do work, cells manage energy resources
Cell Communication. Cell Communication. Cell Communication. Cell Communication. Cell Communication. Chapter 9. Communication between cells requires:
Chapter 9 Communication between cells requires: ligand: the signaling molecule receptor protein: the molecule to which the receptor binds -may be on the plasma membrane or within the cell 2 There are four