Structure and selectivity engineering of the M 1 muscarinic receptor toxin complex-Reference-Cited by-同舟云学术

Structure and selectivity engineering of the M 1 muscarinic receptor toxin complex

Published:2020-07-10 Issue:6500 Volume:369 Page:161-167
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Maeda Shoji¹^ORCID,Xu Jun²,N. Kadji Francois Marie³,Clark Mary J.⁴^ORCID,Zhao Jiawei⁵^ORCID,Tsutsumi Naotaka¹⁶⁷^ORCID,Aoki Junken³^ORCID,Sunahara Roger K.⁴^ORCID,Inoue Asuka³,Garcia K. Christopher¹⁶⁷^ORCID,Kobilka Brian K.¹²^ORCID

Affiliation:

1. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.

2. Beijing Advanced Innovation Center for Structural Biology, School of Life Science, Tsinghua University, Beijing, China.

3. Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Japan.

4. Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.

5. Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.

6. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

7. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

Abstract

Engineering a toxin Developing drugs that target a specific subtype in a G protein–coupled receptor (GPCR) family is a major challenge. Maeda et al. examined the basis of specificity of a snake venom toxin binding to muscarinic acetylcholine receptors (MAChRs), which mediate many functions of the central and parasympathetic nervous systems. They determined a structure that shows why the mamba venom toxin MT7 is specific for one receptor, M 1 AChR, and also explains how it inhibits downstream signaling. Based on this structure, they engineered MT7 to be selective for another receptor, M 2 AChR, instead of M 1 ChR. The toxin may present a promising scaffold for developing specific GPCR modulators. Science , this issue p. 161

Funder

National Institutes of Health

Howard Hughes Medical Institute

G Harold and Leila Y. Mathers Foundation

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference53 articles.

1. Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs