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Unliganded gating of acetylcholine receptor channels.

Abstract：

:We estimated the unliganded opening and closing rate constants of neuromuscular acetylcholine receptor-channels (AChRs) having mutations that increased the gating equilibrium constant. For some mutant combinations, spontaneous openings occurred in clusters. For 25 different constructs, the unliganded gating equilibrium constant (E(0)) was correlated with the product of the predicted fold-increase in the diliganded gating equilibrium constant caused by each mutation alone. We estimate that (i) E(0) for mouse, wild-type alpha(2)beta delta epsilon AChRs is approximately 1.15 x 10(-7); (ii) unliganded AChRs open for approximately 80 micros, once every approximately 15 min; (iii) the affinity for ACh of the O(pen) conformation is approximately 10 nM, or approximately 15,600 times greater than for the C(losed) conformation; (iv) the ACh-monoliganded gating equilibrium constant is approximately 1.7 x 10(-3); (v) the C-->O isomerization reduces substantially ACh dissociation, but only slightly increases association; and (vi) ACh provides only approximately 0.9 k(B)T more binding energy per site than carbamylcholine but approximately 3.1 k(B)T more than choline, mainly because of a low O conformation affinity. Most mutations of binding site residue alphaW149 increase E(0). We estimate that the mutation alphaW149F reduces the ACh affinity of C only by 13-fold, but of O by 190-fold. Rate-equilibrium free-energy relationships for different regions of the protein show similar slopes (Phi values) for un- vs. diliganded gating, which suggests that the conformational pathway of the gating structural change is fundamentally the same with and without agonists. Agonist binding is a perturbation that (like most mutations) changes the energy, but not the mechanism, of the gating conformational change.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Purohit P,Auerbach A

doi

10.1073/pnas.0809272106

subject

Has Abstract

pub_date

2009-01-06 00:00:00

pages

115-20

issue

1

eissn

0027-8424

issn

1091-6490

pii

0809272106

journal_volume

106

pub_type

杂志文章

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