NDLI: Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Content Provider	PubMed Central
Author	Yi, Myunggi Tjong, Harianto Zhou, Huan-xiang
Abstract	Nicotinic AChRs (nAChRs) represent a paradigm for ligand-gated ion channels. Despite intensive studies over many years, our understanding of the mechanisms of activation and inhibition for nAChRs is still incomplete. Here, we present molecular dynamics (MD) simulations of the α7 nAChR ligand-binding domain, both in apo form and in α-Cobratoxin-bound form, starting from the respective homology models built on crystal structures of the acetylcholine-binding protein. The toxin-bound form was relatively stable, and its structure was validated by calculating mutational effects on the toxin-binding affinity. However, in the apo form, one subunit spontaneously moved away from the conformation of the other four subunits. This motion resembles what has been proposed for leading to channel opening. At the top, the C loop and the adjacent β7-β8 loop swing downward and inward, whereas at the bottom, the F loop and the C terminus of β10 swing in the opposite direction. These swings appear to tilt the whole subunit clockwise. The resulting changes in solvent accessibility show strong correlation with experimental results by the substituted cysteine accessibility method upon addition of acetylcholine. Our MD simulation results suggest a mechanistic model in which the apo form, although predominantly sampling the “closed” state, can make excursions into the “open” state. The open state has high affinity for agonists, leading to channel activation, whereas the closed state upon distortion has high affinity for antagonists, leading to inhibition.
Related Links	http://dx.doi.org/10.1073/pnas.0710530105
Ending Page	8285
Page Count	6
Starting Page	8280
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	24
Volume Number	105
Language	English
Publisher	National Academy of Sciences
Publisher Date	2008-06-17
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Design and control of acetylcholine receptor conformational change

Ligand-Induced Conformational Change in the α7 Nicotinic Receptor Ligand Binding Domain

Activation, inactivation, and desensitization of acetylcholine receptor channel complex detected by binding of perhydrohistrionicotoxin

Spontaneous openings of the acetylcholine receptor channel.

Nanosecond-Timescale Conformational Dynamics of the Human α7 Nicotinic Acetylcholine Receptor

Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

Structural effects of quinacrine binding in the open channel of the acetylcholine receptor

Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor

A method for soluble overexpression of the α7 nicotinic acetylcholine receptor extracellular domain

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition

Similar Documents

Design and control of acetylcholine receptor conformational change

Ligand-Induced Conformational Change in the α7 Nicotinic Receptor Ligand Binding Domain

Activation, inactivation, and desensitization of acetylcholine receptor channel complex detected by binding of perhydrohistrionicotoxin

Spontaneous openings of the acetylcholine receptor channel.

Nanosecond-Timescale Conformational Dynamics of the Human α7 Nicotinic Acetylcholine Receptor

Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

Structural effects of quinacrine binding in the open channel of the acetylcholine receptor

Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor

A method for soluble overexpression of the α7 nicotinic acetylcholine receptor extracellular domain

Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: Insight into channel activation and inhibition