Detergent solubilised 5 TMD binds pregnanolone at the Q245 neurosteroid potentiation site.
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1 Supplementary Figure 1 Detergent solubilised 5 TMD binds pregnanolone at the Q245 neurosteroid potentiation site. (a) Gel filtration profiles of purified 5 TMD samples at 100 nm, heated beforehand for 1 hr at a range of temperatures to determine the decay of the pentameric peak protein species (a variable peak of protein aggregate is observed at 0.8 ml). (b) Thermostability plots of the pentameric peak decay with increasing temperature for 5 TMD and its Q245L and Q245W mutants. Data points are from single melting experiments. (c) and (d) Gel filtration profiles for 5 TMD and its Q245W mutant, respectively, showing the pentamer peak after heating to a temperature sufficient to cause 70 % peak decay (73 C for 5 TMD ; 77 C for Q245W), and subsequent dose-dependent stabilisation of the protein by increasing concentrations of pregnanolone. Remarkably, increasing pregnanolone concentrations drive 5 TMD stability very close to its no heating (4 C) level. (e) Pregnanolone dose-response curves for thermostabilisation of 70 % decayed 5 TMD and its Q245L and Q245W mutants. NOTE: The solubility limit of pregnanolone in this buffer is 30 M. Each data point represents mean s.e.m. of n = 3 experiments, each data point being from separate aliquots of purified protein.
2 Supplementary Figure 2 Architecture of the 5 TMD -Nb25 complex. (a) Side-on view of pregnanolone-bound (blue stick representation, in dashed box) 5 TMD structure. Nb25 molecules are shown in green spacefill representation. Principal (P) and complementary (C) sides of one intersubunit interface are labelled. (b) Close-up of Nb25 bound across the P/C interface near the neurotransmitter site. Dashed lines denote subunit/nanobody boundaries. Nb25 is shown in green, with a yellow CDR3 loop. The 5 TMD P face is coloured in blue, with a cyan loop-c. (c) Close-up of interactions between the 5 TMD neurotransmitter-binding loop-c (cyan) and the antigen recognising CDR3 loop of Nb25 (yellow). The closed conformation of the loop-c mimics that of the agonist-bound GABA A R- 3 (beige overlay, PDB ID: 4COF) rather than the open loop-c conformation of the antagonist-bound glycine receptor (grey overlay, PDB ID: 5CFB). (d) Binding footprint of Nb25 peeled 180 away from 5 TMD. The hypervariable Nb25 regions, CDR1 (dashed circle), CDR2 (double-bordered ellipse) and CDR3 (single bordered ellipse), map broadly over the 5 TMD 6-7 loop, loop-f and loop-c, respectively. Salt-bridge contacts are shown in red (Asp/Glu) and purple (Arg/Lys), polar contacts in cyan and van der Waals contacts in orange. Each Nb25 molecule forms ~1080 Å 2 interfaces with 5 TMD, roughly equally distributed between P/C faces. (e) and (f) Structural alignment of 5 TMD pregnanolone-bound (blue) with apo (grey) or GABA A R- 3 (beige) ECDs, respectively. RMSD values over 204 equivalent ECD C positions are 0.19 Å (pregnanolone-bound vs apo 5 TMD ) and 0.45 Å (pregnanolone-bound 5 TMD vs GABA A R- 3). (g) Bar chart showing that the amount of potentiation of EC 10 histamine (his) by 10 M pregnanolone (preg) is the same in the presence or absence of 50 M Nb25. Each data point represents mean s.e.m. of n = 5 experiments, each measurement being from different cells.
3 Supplementary Figure 3 Crystallographic quality control for pregnanolone binding to 5 TMD. (a) SigmaA-weighted 2F o -F c (blue, contoured at 2 ) and F o -F c (green/red contoured at +3 /-3 ) electron density maps following refinement in the absence of pregnanolone. (b) The same electron density maps and contour levels following refinement in the presence of pregnanolone. (c) Final model, showing pregnanolone (cyan) bound between the principal (P) and complementary faces (C) of adjacent subunits (PDB chains C and B respectively). Thick dotted lines indicate contacts within hydrogen-bonding distance. Thin dotted lines mark the inter-subunit boundary. (d) Overlay of the five pregnanolone molecules in 5 TMD (cyan as in (c), the other four, at equivalent inter-subunit sites, in green). Pregnanolone molecules were overlaid by superposing the complementary chains from each site. Putative hydrogen bond distances between the pregnanolone 3 -hydroxyl and the M1 Gln245 O range from Å. Putative hydrogen bond distances between the pregnanolone C20 ketone and the Thr 309 hydroxyl range from Å.
4 Supplementary Figure 4 Impact of residue mutations lining the pregnanolone binding site on potentiation, and location of -subunit M4 residues Asn410 and Tyr413 outside the site. (a) Dose response curves for pregnanolone potentiation of EC 10 histamine responses for 5 TMD T287K and with mutations to single residues lining the pregnanolone binding site. (b) and (c) Pregnanolone bound to the intersubunit site between M3 residues on the principal face (indicated by P in box) and M1 residues on the complementary face (indicated by C in box). The complementary face is shown in (a) cartoon or (b) cartoon with overlaying space-fill to highlight the top border of the pocket (dashed line). Putative hydrogen bonds between pregnanolone and 5 TMD residues are indicated by dotted lines. Two M4 residues, Asn410 and Tyr413 (green labels) that have previously been implicated in pregnanolone binding by mutagenesis studies are shown to reside outside the site. M1 Ile238 and M4 Phe406 (blue labels) close the top of the site and bisect between M1 Gln245 and M4 Asn410 and Tyr413. Each data point represents mean s.e.m. Pregnanolone EC 50 n number: WT n = 5, Q245S n = 8, V246A n = 4, W249L n = 7, I305 n = 3, T309A n = 3. Each n EC 50 measurement is from different cells.
5 Supplementary Figure 5 Pregnanolone binding mode and 5 TMD potentiation by neurosteroids. (a) Top panel: structural formula of pregnanolone. Lower panel: the neurosteroid binding site in the 5 TMD structure with pregnanolone bound (blue sticks, shown within SigmaA-weighted 2F o -F c electron density map contoured at 1.3, grey mesh) overlaid with computationally docked pregnanolone (yellow sticks). (b) Dose response curves for pregnanolone (3 5 ), allopregnanolone (3 5 ) and epipregnanolone (3 5 ) potentiation of EC 10 histamine responses for 5 TMD T287K. Each data point represents mean s.e.m. Steroid EC 50 n number: WT n = 5, allopregnanolone n = 3, epipregnanolone n = 10. Each n EC 50 measurement is from different cells.
6 Supplementary Figure 6 Comparison between pregnanolone-bound 5 TMD and GABA A R- 3 channel pore profiles and hydrophobicity. Cross-sections showing the pore-lining M2 helices and the solvent-accessible surface mapped and colored according to the Eisenberg hydrophobicity scale (Eisenberg, D., Schwarz, E., Komaromy, M. & Wall, R., J. Mol. Biol. 179, , 1984) (pale green is hydrophobic; bright green is polar). Panels a-c show 5 TMD and panels d-f show GABA A R- 3 (PDB ID: 4COF). (a) and (d) Sagittal slices along the longitudinal pore axis. The dashed lines mark the beginning of the views shown in c and f. (b-c) and (e-f) Top-down views of the pore. View points are from the dashed lines shown a and d for b and e, respectively, and from further down the pore, just above the 2 ring, for c and f. The desensitisation gate of 5 TMD has two constrictions, the hydrophobic 2 Val260 ring (pale green) and the -2 Pro256 ring. In GABA A R- 3, the desensitisation gate has a single constriction, formed by the -2 Ala248 ring.
7 Supplementary Figure 7 Crystal packing of pregnanolone-bound and apo 5 TMD. (a) Pregnanolone-bound 5 TMD (space group I23) and (b) apo 5 TMD (space group C2). Ligands are not shown, for clarity. Coloring scheme: ECD blue, TMD red, Nb25 green. Dashed boxed areas in the left-hand panels are enlarged as close-ups in the right-hand panels. The M1-M2 linker (yellow) is not involved in crystal contacts.
8 Supplementary Figure 8 Comparison between the 5 TMD pregnanolone-binding site and GluCl TMD modulator site locations. Top-down (top panel) and side-on (lower panel) views of two neighbouring subunit TMDs. (a) Pregnanolonebound 5 TMD. (b) Ivermectin-bound GluCl (PDB ID: 3RIF). Boxed P and C letters indicate principal and complementary faces, respectively. Whilst pregnanolone occupies a location in the lower half, and on the outer surface of the TMD, the ivermectin site is in the top half of the GluCl TMD and ivermectin inserts deeper in the intersubunit interfaces.
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