Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling-Reference-Cited by-同舟云学术

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling

Published:2021-05-21 Issue:6544 Volume:372 Page:808-814
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Israeli Hadar¹²^ORCID,Degtjarik Oksana¹^ORCID,Fierro Fabrizio³⁴^ORCID,Chunilal Vidicha⁵^ORCID,Gill Amandeep Kaur⁵^ORCID,Roth Nicolas J.⁵,Botta Joaquin⁵^ORCID,Prabahar Vadivel¹^ORCID,Peleg Yoav⁶^ORCID,Chan Li F.⁵^ORCID,Ben-Zvi Danny²^ORCID,McCormick Peter J.⁵^ORCID,Niv Masha Y.³⁴^ORCID,Shalev-Benami Moran¹^ORCID

Affiliation:

1. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.

2. Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University–Hadassah Medical School, Jerusalem, Israel.

3. The Faculty of Agriculture, Food and Environment, The Hebrew University, Rehovot, Israel.

4. The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem, Israel.

5. Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary, University of London, Charterhouse Square, London, UK.

6. Structural Proteomics Unit (SPU), Life Sciences Core Facilities (LSCF), Weizmann Institute of Science, Rehovot 7610001, Israel.

Abstract

To eat or not to eat Melanocortin receptor 4 (MC4R) plays a role in regulating food intake: Its activation by a stimulating hormone inhibits appetite, whereas binding to a natural antagonist promotes appetite. Complementing a recent structure of MC4R in an inactive conformation, Israeli et al. present the structure bound to setmelanotide, a weight-control drug, and its G protein–signaling partner (see the Perspective by Farooqi). This work reveals the mechanism of MC4R activation and explains why setmelanotide acts as a potent agonist, whereas a structurally similar compound, SHU9119, is an inhibitor. The structure also provides insight into the contribution of mutations in MCR4 to weight-regulation disorders. Science , abf7958, this issue p. 808 ; see also abi8942, p. 792

Funder

University of Kentucky

Biotechnology and Biological Sciences Research Council

European Cooperation in Science and Technology

Israel Science Foundation

Mauritius Research Council

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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