Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor.

Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor. Research Abstract Details 

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Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor. Abstract Text:

Amanda L Cashin,Michael M Torrice,Kathryn A McMenimen,Henry A Lester,Dennis A Dougherty,

The nicotinic acetylcholine receptor and related Cys-loop receptors are ligand-gated ion channels that mediate fast synaptic transmission throughout the central and peripheral nervous system. A highly conserved aspartate residue (D89) that is near the agonist binding site but does not directly contact the ligand plays a critical part in receptor function. Here we probe the role of D89 using unnatural amino acid mutagenesis coupled with electrophysiology. Homology modeling implicates several hydrogen bonds involving D89. We find that no single hydrogen bond is essential to proper receptor function. Apparently, the side chain of D89 establishes a redundant network of hydrogen bonds; these bonds preorganize the agonist binding site by positioning a critical tryptophan residue that directly contacts the ligand. Earlier studies of the D89N mutant led to the proposal that a negative charge at this position is essential for receptor function. However, we find that receptors with neutral side chains at position 89 can function well, if the side chain is less perturbing than the amide of asparagine (nitro or keto groups allow function) or if a compensating backbone mutation is introduced to relieve unfavorable electrostatics.

Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor. Publishing Authors By Initials

AL Cashin,MM Torrice,KA McMenimen,HA Lester,DA Dougherty,

For similar animals: chordata: vertebrates: amphibia: anura: pipidae: xenopus: xenopus laevis research abstracts see: animals: chordata: vertebrates: amphibia: anura: pipidae: xenopus: xenopus laevis research

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Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biochemistry

VOLUME: 46

Page Numbers: 630-9

Journal Abbreviation: Biochemistry

ISSN: 0006-2960

DAY: 23

MONTH: Jan

YEAR: 2007

Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 370623

Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor. Keywords Mesh Terms:

KEYWORDS: Xenopus laevis

MESH TERMS: chemistry

Chemical & Substance for Abstract: Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor. Information

Substance Name: Tryptophan

Registry Number: 73-22-3

Grant and Affiliation Information for Chemical-scale studies on the role of a conserved aspartate in preorganizing the agonist binding site of the nicotinic acetylcholine receptor.

AFFILIATION: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS 34407

ACRONYM: NS

MEDLINETA: Biochemistry

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