Nature Structural & Molecular Biology: doi: /nsmb.1933
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1 The structural basis of open channel block in a prokaryotic pentameric ligand-gated ion channel Ricarda J. C. Hilf, Carlo Bertozzi, Iwan Zimmermann, Alwin Reiter, Dirk Trauner and Raimund Dutzler a GLIC ELIC α7achr αachr βachr -1' 2' 6' 9' 13'16' TSYEANVTLVVSTLIAHIAFNILVETNLPKT ESFSERLQTSFTLMLTVVAYAFYTSNILPRL ADSGEKISLGITVLLSLTVFMLLVAEIMPAT TDSGEKMTLSISVLLSLTVFLLVIVELIPST PDAGEKMSLSISALLALTVFLLLLADKVPET Supplementary Figure 1 Sequence conservation and ph activation of GLIC. a Sequence alignment of the pore region of the plgics from Gloeobacter violaceous (GLIC), Erwinia chrysanthemi (ELIC), the homopentameric human α7 acetylcholine receptor (α7achr), and the α and β chains of the heteropentameric muscle-type acetylcholine receptor (AChR) from Torpedo marmorata. Conserved positions contributing to the pore lining are highlighted in red. The previously introduced numbering for the pore of the nachr is shown above. For GLIC -1' corresponds to position Glu221. b Two electrode voltage clamp recordings of Xenopus oocytes expressing GLIC. Currents were recorded at -60 mv. The ph of bath solutions is indicated above. The solution was changed back to ph 7 after each activation step. c Open probability of GLIC plotted as function of the proton concentration. The currents were normalized to the value at ph 4. The averages of 5 oocytes and their standard deviations are shown. The solid line shows a fit to a hill equation with a coefficient of 3.0.
2 Supplementary Figure 2 Block by QA compounds. (a) Reversible block of currents mediated by GLIC in response to the addition of 10 mm TBA. Currents were recorded at -80 mv. (b) GLICmediated macroscopic currents recorded by the inside-out patch clamp technique at 40 mv. The pipette solution was at ph 5.5. The perfusion with bath solution (at ph7) containing 10 mm TBA or 10 mm Cd 2+ is indicated. (c) Dependence of channel block on the size of the QA compounds and the ph of the extracellular solution. IC 50 values of different QA compounds (left, measured at ph4.5) and the dependence of TBA block on the ph of the bath solutions (right) are shown. Data
3 was recorded at -80 mv, the average of at least 12 independent measurements and their standard deviation are shown. (d) Dose-response curves of TBSb and (e) TEAs block recorded from GLIC expressed in Xenopus laevis oocytes by 2-electrode voltage clamp at an extracellular ph of 4.5. The averages of currents from 7 (TBSb) and 5 (TEAs) oocytes and their standard deviations are shown. Measurements at different membrane potentials (ranging from -120 to -40 mv in 20 mv steps) are colored as indicated with a fit to a single site binding isotherm shown in the same color. (f) Voltage dependence of TEAs and TBSb block. The voltage dependence of TEA and TBA are shown for comparison. (g) Distribution of anomalous difference electron densities of QA analogues bound to GLIC. The electron densities (ρ) were sampled in the transmembrane region along the pore axis and normalized to their maximum value. The hydrophobic core of the membrane is indicated (grey box). The Cα positions of pore residues are marked. (h) Structure of the pore region of GLIC in complex with tetramethylarsonium (TMAs). The orange mesh shows the anomalous difference electron density calculated at 4.0 Å and contoured at 5σ. -80 IC 50 / mm n ph Nr WT TBA WT TBA WT TBA WT TEA WT TMA WT TBSb WT TEAs WT TPA E221A TBA E221Q TBA E221D TBA T225A TBA S229A TBA E221A TBA E221Q TBA E221D TBA T225A TBA S229A TBA E221A TEA E221Q TEA E221D TEA WT Lidoc WT Cd E221A Cd 2+ n.d. n.d T225A Cd S229A Cd Supplementary Table 1 Electrophysiology. IC 50 values (at -80mV) were obtained from a fit of the averaged normalized currents to a single site adsorption isotherm (for n=1), or to a hill equation (with coefficient n for n<1). The number of independent measurements and the ph of the extracellular solution are indicated.
4 Supplementary Figure 3 Binding of QA compounds to GLIC mutants. The labeling is as in Supplementary Fig. 3g. (a) Distribution of anomalous difference electron densities of TBSb bound to the pore mutants S229A and T225A. The positions of TBSb and Cs + bound to WT are shown for comparison. (b) Distribution of anomalous difference electron densities of TBSb bound to mutants of Glu221. The position of TBSb bound to WT is shown for comparison (dashed line). (c) Distribution of anomalous difference electron densities of TEAs bound to mutants of Glu221. The position of TEAs bound to WT is shown for comparison (dashed line). Supplementary Figure 4 Lidocaine block. (a) Voltage dependence of lidocaine block suggesting that the inhibitor binds at an electrical distance zδ = The voltage dependence of TBA is shown for comparison. (b) Distribution of anomalous difference electron densities of Br-lidocaine bound to GLIC. The positions of QA analogues are shown for comparison. The electron density for Br-lidocaine corresponds to the bromide atom attached to the aromatic ring. The extended binding region of the blocker is indicated by two connected circles. (c) Structure of the pore region of GLIC in complex with Br-lidocaine. A structure of the inhibitor modeled into the pore is shown in space-filling representation.
5 Supplementary Figure 5 Transition metal ion block of GLIC. (a) Fraction of the initial currents recovered after subsequent steps of incubation with Cd 2+ at increasing concentrations. Cd 2+ concentrations (mm) are indicated above. The currents were measured at -80mV after reequilibration with bath solution at ph 4.0. The average of 10 measurements and their standard deviations are shown. (b) Voltage dependence of Cd 2+ block suggesting that the divalent ion binds at an electrical distance of zδ = (c) Representative current-voltage relationship of GLIC recorded from an extracellular solution (ph 4.0) containing 75 mm Cd 2+ (blue). The currents after reequilibration in solutions without Cd 2+ are shown in grey. Representative currentvoltage relationship of GLIC (d) and the pore mutant E221A (e) recorded from an extracellular solution (ph 4.0) containing 200 mm Zn 2+ (blue). The currents after reequilibration in solutions without Zn 2+ are shown in grey.
6 Supplementary Figure 6 Transition metal binding to GLIC. (a) Cα representation of GLIC in complex with Cd 2+. The extracellular domain is colored red, the pore domain green. The front subunit is removed for clarity. The anomalous difference electron density of Cd 2+ was calculated at 4.0 Å and contoured at 5 σ and is shown as blue mesh. (b) Distribution of anomalous difference electron densities of Cd 2+ in the pore region. Cd 2+ ions bind to two sites indicated as blue peaks. The positions of Zn 2+ and Cs + are shown for comparison. (c) Cα representation of the pore mutant E221A in complex Cd 2+. The anomalous difference electron density of Cd 2+ was calculated at 4.0 Å and contoured at 5 σ and is shown as blue mesh. (d) Structure of the pore region of S229A in complex with Cd 2+. The anomalous difference electron density of Cd 2+ was calculated at 4.5 Å and contoured at 5 σ and is shown as blue mesh. (e) Cα representation of GLIC in complex Zn 2+. The anomalous difference electron density of Zn 2+ was calculated at 4.0 Å and contoured at 4.5 σ and is shown as red mesh. (f) Cα representation of E221A in complex Zn 2+. The anomalous difference electron density of Zn 2+ was calculated at 4.5 Å and contoured at 4.5 σ and is shown as red mesh.
7 Supplementary Figure 7 Role of Glu221 in Cd 2+ binding. Model of the binding region of Cd 2+ ions in the pore of GLIC. Three possible side-chain conformations of Glu221 are shown in views from within the membrane (top) and from the intracellular side (bottom). Cd 2+ ions are shown in blue. Glu221 of one subunit is labeled (*). Left: conformation as observed in the crystal structure of GLIC crystallized at ph 4.0 and determined 3.1 Å resolution (PDB code 3EHZ). Center: conformation where the Glu side chains interact with the ions in the intracellular binding site. Right: The carboxylate side chains of Glu221 are oriented away from the pore and are not in direct interaction with the ions. Supplementary Figure 8. The synthesis of a brominated Br-lidocaine synthesis version of lidocaine from 2,6-dimethylaniline (1) is illustrated. (1) is first selectively brominated in the 4 position, using the hexamethylenetetramine-bromine complex (HMTAB) to give 4-Bromo-2,6- dimethylaniline (2). This highly substituted aniline is next converted to amide (3), the immediate precursor of lidocaine, by treatment with the bifunctional reagent 2-chloroacetylchloride (4) in the presence of Huenigs base. The reaction of amide (3) with diethylamine completes the synthetic sequence. (1, 2, 3, 5) were purified by flash chromatography on a SiO 2 matrix and analyzed by standard spectroscopic techniques.
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