M2

Figure 11.3. Helical net plot of the amino acid sequence around the membrane-spanning segment M2 (Torpedo a subunit). The leucine residue near the middle of the membrane (yellow) is the conserved leucine L251 (at the 9' position), which may be involved in forming the gate of the channel. The dots denote other residues that have been shown to affect the binding affinity of an open channel blocker (17, 18) and ion flow through the open pore (19). The numbers shown refer to the numbering scheme for M2 residues used in the text.

Figure 11.3. Helical net plot of the amino acid sequence around the membrane-spanning segment M2 (Torpedo a subunit). The leucine residue near the middle of the membrane (yellow) is the conserved leucine L251 (at the 9' position), which may be involved in forming the gate of the channel. The dots denote other residues that have been shown to affect the binding affinity of an open channel blocker (17, 18) and ion flow through the open pore (19). The numbers shown refer to the numbering scheme for M2 residues used in the text.

Figure 11.6. The binding site of AChBP. The ligand (HEPES) is in yellow. Blue and red regions denote the inner- and outer-sheet parts of the p-sandwich (30). The views in (a) and (b) are with the fivefold axis vertical, and the "'membrane" at the bottom. (a)The structure shown is analogous to the binding site of the Torpedo or human ctl subunit, to which the numbering of identified residues refers. Numbers in parentheses refer to AChBP. (b) Surface of the neighboring protomer that faces the binding site of the AChBP. In the receptor this would be part of the y, e, or 6 subunit. Numbers in parentheses refer to the AChBP. W53 aligns with W55 in mouse y, €, and 6 nicotinic receptor subunits, but most of the residues have no obvious analog in the 7, e, or 6 subunits of the nicotinic receptor. For example, Q55 aligns with mouse 7E57, tG57, and 8D57; LI 12 aligns with mouse 7YII7 or ST119, and Y164 is A or G in the nicotinic subunits.

Figure 11.4. Three subunits of the Lymnaea AChBP viewed perpendicular to the fivefold axis of symmetry and from the outsKie oft the pfctftamer. The "inner ancl outer sheets of the p-sandwich are blue and red, respectively, whereas the putative ligand HEPES is purple. The approximate positions of the a carbons of residues discussed in the text are marked with arrows on the foremost subunit. The approximate positions of the cell membrane and of the M2-M3 loop are shown diagrammatically. The inner fi-sheet (blue) is thought to rotate after agonist binding and to interact with the M2-M3 loop (as indicated by the asterisk).

Figure 11.6. The binding site of AChBP. The ligand (HEPES) is in yellow. Blue and red regions denote the inner- and outer-sheet parts of the p-sandwich (30). The views in (a) and (b) are with the fivefold axis vertical, and the "'membrane" at the bottom. (a)The structure shown is analogous to the binding site of the Torpedo or human ctl subunit, to which the numbering of identified residues refers. Numbers in parentheses refer to AChBP. (b) Surface of the neighboring protomer that faces the binding site of the AChBP. In the receptor this would be part of the y, e, or 6 subunit. Numbers in parentheses refer to the AChBP. W53 aligns with W55 in mouse y, €, and 6 nicotinic receptor subunits, but most of the residues have no obvious analog in the 7, e, or 6 subunits of the nicotinic receptor. For example, Q55 aligns with mouse 7E57, tG57, and 8D57; LI 12 aligns with mouse 7YII7 or ST119, and Y164 is A or G in the nicotinic subunits.

Figure 11.9. Arrangements of the inner (blue) and outer (red) 3-sheet parts of the (a) a and (b) non-a sub-units (see Figs. 11.4 and 11.6), after fitting to the densities in the 4.6-A map of the receptor. The arrangement of the sheets in the a subunits switches to that of the non-a sheets when ACh binds. The views are in the same direction, toward the central axis from outside the pentamer. Arrows and angles in A denote the sense and magnitudes of the rotations relating the a to the non-a sheets. The traces are aligned so that the inner sheets are superimposed. [Adapted from Unwin et al. (30).l

«Y190F similar loss of both affinity and gating a1

«N217K gain of affinity mainly (SCCMS)

DIE TYHFVMQRL PLyf ] V

DIE TYHFVMQRL PLyf ] V

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