The dynamic process of GPCR activation: Insights from the human β 2 AR

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1 The structural basis of G protein coupled receptor signaling The dynamic process of GPCR activation: Insights from the human β 2 AR Brian Kobilka Department of Molecular and Cellular Physiology Brian Kobilka Molecular Stanford and Cellular Physiology Stanford University

2 Autonomic nervous system regulates cardiovascular, pulmonary and endocrine function. Therapeutic targets for intensive care medicine Sympathetic (9 Adrenergic receptor subtypes) Adrenaline and Noradrenaline Parasympathetic (5 Muscarinic receptor subtypes) Acetylcholine

3 Autonomic nervous system regulates cardiovascular, pulmonary and endocrine function. Therapeutic targets for intensive care medicine Sympathetic (9 Adrenergic receptor subtypes) Adrenaline and Noradrenaline Parasympathetic (5 Muscarinic receptor subtypes) Acetylcholine β adrenergic Receptor

4 Autonomic nervous system regulates cardiovascular, pulmonary and endocrine function. Therapeutic targets for intensive care medicine Sympathetic (9 Adrenergic receptor subtypes) Adrenaline and Noradrenaline Parasympathetic (5 Muscarinic receptor subtypes) Acetylcholine β adrenergic Receptor M2 Muscarinic Receptor

5 Autonomic nervous system regulates cardiovascular, pulmonary and endocrine function. Therapeutic targets for intensive care medicine Sympathetic (9 Adrenergic receptor subtypes) Adrenaline and Noradrenaline Parasympathetic (5 Muscarinic receptor subtypes) Acetylcholine β adrenergic Receptor M2 Muscarinic Receptor µ Opioid Receptor

6 What are G protein coupled receptors? Integral membrane proteins Detect hormones, neurotransmitters, ions, light, odors and flavors Transmit signals across the cell membrane to change the behavior of cells Over 800 members of the GPCR family in the human genome Largest class (~40%) of pharmaceutical targets Agonist binding G protein coupling and nucleotide exchange Activated G protein subunits regulate effector proteins GTP hydrolysis and inactivation of Gα protein G protein GPCR-G Protein Cycle

7 Largest family of membrane proteins in the human genome

8 GPCR Family Tree The Rhodopsin Family GPCRs: 701 Total 241 Non-olfactory Neuropeptide THRH Oxytocin receptor Chemokine Angiotensin Bradykinin Rhodopsin Adrenergic Dopamine Serotonin Histamine Muscarinic FSH, LH and TSH receptors Fredriksson et al. Mol Pharm 2003

9 Rhodopsin Family Tree The Rhodopsin Family (241 Nonolfactory, Total of 701) Adrenergic Muscarinic Serotonin Dopamine

10 G Protein Coupled Receptors Challenges Drug Discovery Many targets that share sequence and structural homology Complex signaling behavior o Multiple cell-specific signaling pathways o Different types of ligands (Efficacy) o Receptor oligomers (homo- and heteromers)

11 GPCR Signaling Ca 2+ Channel Adenylyl Cyclase

12 GPCR Signaling Ca 2+ Channel Adenylyl Cyclase Basal

13 GPCR Signaling Ca 2+ Channel Adenylyl Cyclase Basal

14 GPCR Signaling Ca 2+ Channel Adenylyl Cyclase Basal

15 GPCR Signaling Ca 2+ Channel Adenylyl Cyclase Basal

16 GPCR Signaling Ca 2+ Channel Adenylyl Cyclase Basal

17 Agonist binding G protein coupling and nucleotide exchange Activated G protein subunits regulate effector proteins GTP hydrolysis and inactivation of Gα protein GPCR-G Protein Cycle

18 Agonist binding G protein coupling and nucleotide exchange Activated G protein subunits regulate effector proteins GTP hydrolysis and inactivation of Gα protein GPCR-G Protein Cycle

19 Outline Challenges in obtaining GPCR crystals Inactive state structures Active state structures Agonist binding G protein coupling and nucleotide exchange Activated G protein subunits regulate effector proteins GTP hydrolysis and inactivation of Gα protein GPCR-G Protein Cycle

20 Biochemistry Spectroscopy Crystallography

21 Crystals grown from wild-type β 2 AR June 05 Nov c5 249d4 50µm 247d3

22 50 µm

23 Conventional beam (100 micron)

24 ESRF microfocus beamline ID13, July 2005 Microfocus beam (5 micron) Gebhard Schertler

25 ESRF microfocus beamline ID13, July 2005 Microfocus beam Gebhard Schertler

26 Insights from fluorescence, EPR and NMR spectroscopy studies TM6 Ansgar Philippsen & Ron Dror (D.E. Shaw Research) TM6 undergoes largest structural changes following agonist binding Agonist binding and activation occur through a series of conformational intermediates Agonists and partial agonists stabilize distinct conformational states Agonists alone do not stabilize a single active conformation

27 Gs β 2 AR No ligand β 2 AR + agonist β 2 AR + agonist + Gs

28 Gs β 2 AR No ligand β 2 AR + agonist β 2 AR + agonist + Gs

29 Gs β 2 AR No ligand β 2 AR + agonist β 2 AR + agonist + Gs Structural insights from fluorescence, EPR and NMR spectroscopy Gs

30 TM5 Purified protein TM6 Conformationally uniform GPCR High-quality crystal

31 TM5 Purified protein TM6 Conformationally heterogeneous GPCR Poor quality crystal

32 Challenges for crystallography Protein dynamics TM5 TM6

33 Challenges for crystallography Protein dynamics Little polar surface TM5 TM6

34 Challenges for crystallography Protein dynamics Little polar surface Stabilize and increase polar surface Antibodies Protein Engineering

35 A B 3.5 Å 50µ m Primitive monoclinic a = Å b = 65.5 Å c = Å β = 95.8 β 2 AR-

36 β 2 AR-Fab5 complex 3.0Å 50µm Space group C2 Unit cell parameters a=336.9 Å b=48.6 Å c=89.0 Å β=104.6º one β2ar-fab complex in the asymmetric unit.

37 β 2 AR- Rock II Crystals

38 Approaches for GPCR crystallogenesis: Antibodies and protein engineering Lipid-based media: bicelles and lipidic cubic phase 2007 Søren Rasmussen Dan Rosenbaum TM5 TM6 TM5 TM6 Fab

39 Approaches for GPCR crystallogenesis: Antibodies and protein engineering Lipid-based media: bicelles and lipidic cubic phase 2007 Søren Rasmussen Dan Rosenbaum TM5 TM6 TM5 TM6 TM5 TM6 Fab

40 β 2 AR INACTIVE Inverse Agonist Fab

41 β 2 AR INACTIVE Inverse Agonist Fab Other inactive state structures Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

42 β 2 AR INACTIVE Inverse Agonist Other Approaches Thermostabilization through alanine scanning mutations β 1 AR, Adenosine A2A Tate and Schertler Fab Other inactive state structures Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

43 Inverse Agonist β 2 AR INACTIVE β 2 AR ACTIVE Other Approaches Thermostabilization through alanine scanning mutations β 1 AR, Adenosine A2A Tate and Schertler Rhodopsin (native) Schertler (2D crystals) Palczewski and Okada (3D) Ernst and Hofmann (Opsin) Fab Other inactive state structures Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

44 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Fab Other inactive state structures Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

45 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Unable to grow crystals of agonist bound receptor Fab Other inactive state structures Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

46 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Agonist (covalent) Fab Other inactive state structures Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

47 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Agonist (covalent) Agonist alone does not fully stabilize active state β 2 AR β 2 AR + Agonist Fab Other inactive state structures Stabilizing protein Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

48 Conventional vs. Camelid IgG Jan Steyaert Els Pardon

49 Conventional vs. Camelid IgG Fab fragment Nanobody Jan Steyaert Els Pardon

50 Generation of conformationally sensitive antibodies to the β 2 AR (Collaboration with Jan Steyaert and Els Pardon, Free University Brussels) Purification of functional β 2 AR antigen Reconstitution into proteoliposomes at a high protein/lipid ratio Immunize llamas > prepare nanobody-display library > select binders Immunization Phage display (Immunogenic)

51 Nanobody vs. Fab 7 of 16 Nb clones exhibited: 1. Agonist dependent binding to β 2 AR 2. Stabilize an active conformation 3. Stabilize agonist high-affinity state

52 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Agonist (covalent) Agonist Fab Other inactive state structures Nb80 Stabilizing protein Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

53 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Agonist (covalent) Partial Agonist Agonist Fab Nb71 Other inactive state structures Nb80 Stabilizing protein Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin)

54 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Agonist (covalent) Partial Agonist Agonist Fab Nb71 Other inactive state structures Nb80 Stabilizing protein Active M2 Muscarinic Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin) Nb9-8

55 β 2 AR INACTIVE β 2 AR ACTIVE Inverse Agonist Agonist (covalent) Partial Agonist Agonist Fab Nb71 Other inactive state structures Nb80 Active M2 Muscarinic Pipette M2 Muscarinic M3 Muscarinic δ Opioid µ Opioid PAR1 (Haga and Kobayashi) (Jurgen Wess) (Sebastien Granier) (Shaun Coughlin) Nb9-8

56 Technical contributions to crystallizing the β 2 AR-Gs complex High-affinity agonist BI (1 of ~ 60 screened) Detergent: MNG-3 (long-term storage, aids transition into LCP) Lipidic cubic phase crystallography: New mesophase lipid (7.7 MAG) to accommodate G protein (provided by Martin Caffrey) Nanobody to stabilize G protein complex (Jan Steyaert) Protein engineering: amino terminal T4 Lysozyme Project guided by data from negative stain single particle EM (Georgios Skiniotis) Mini-beam X-ray technology (GM/CA, Argonne National Labs)

57 Microcrystallography GM/CA-CAT at Argonne National Labs β 2 AR-Gs complex Andy Kruse, Brian DeVree, Søren Rasmussen me Roger Sunahara Returning from Argonne with final data set April 2011

58 Gsαβγ β 2 AR

59 Active state of β 2 AR Cytoplasmic View 2Å TM5 TM5 TM6 14Å 14Å TM6 β 2 AR - Inactive β 2 AR-Gs

60 β 2 AR Gsαβγ Inactive Gα Ras-like domain GDP α-helical domain Interactions between the β 2 AR and Gs promote GDP release.

61 β 2 AR Gsαβγ Inactive Active

62 β 2 AR α helical domain Gsαβγ Active Inactive

63 Computational approaches to drug discovery

64 Ca 2+ Channel Adenylyl Cyclase Future Directions Efficacy Basal

65 β 2 AR-Gs Team GPCR Workshop, Maui, Dec. 2011

66 Many Thanks Tong Sun Kobilka Kobilka lab students, postdoctoral fellows and collaborators ( ) Bill Weis and Roger Sunahara Stanford Søren Rasmussen Foon Sun Thian Tong Sun Kobilka Yaozhong Zou Andrew Kruse Ka Young Chung Jesper Mathiesen Bill Weis GM/CA staff at Argonne β 2 AR-Gs Team University of Michigan Brian DeVree Diane Calinski Gerwin Westfield Georgios Skiniotis Roger Sunahara University of Wisconsin Pil Seok Chae Sam Gellman We will miss Virgil Woods (UCSD), Free University of Brussels Els Pardon Jan Steyaert Trinity College Dublin Joseph Lyons Syed Shah Martin Caffrey Financial Support NIH NINDS and NIGMS Gifts from: Mathers Foundation Lundbeck

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