한빛사논문
- 조회903
Amal El Daibani1,2,11, Joseph M. Paggi3,11, Kuglae Kim4,10,11, Yianni D. Laloudakis3,11, Petr Popov5, Sarah M. Bernhard1,2, Brian E. Krumm4, Reid H. J. Olsen4, Jeffrey Diberto4, F. Ivy Carroll6, Vsevolod Katritch7, Bernhard Wünsch8, Ron O. Dror3,9 & Tao Che1,2
1Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
2Center for Clinical Pharmacology, University of Health Sciences & Pharmacy and Washington University School of Medicine, Saint Louis, MO, USA.
3Department of Computer Science, Stanford University, Stanford, CA, USA.
4Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
5iMolecule, Skolkovo Institute of Science and Technology, Moscow, Russia.
6Research Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709, USA.
7Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
8Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, 48149 Münster, Germany.
9Departments of Molecular and Cellular Physiology and of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
10Present address: Department of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
11These authors contributed equally: Amal El Daibani, Joseph M. Paggi, Kuglae Kim, Yianni D. Laloudakis.
Corresponding authors : Correspondence to Ron O. Dror or Tao Che.
Abstract
The κ-opioid receptor (KOR) has emerged as an attractive drug target for pain management without addiction, and biased signaling through particular pathways of KOR may be key to maintaining this benefit while minimizing side-effect liabilities. As for most G protein-coupled receptors (GPCRs), however, the molecular mechanisms of ligand-specific signaling at KOR have remained unclear. To better understand the molecular determinants of KOR signaling bias, we apply structure determination, atomic-level molecular dynamics (MD) simulations, and functional assays. We determine a crystal structure of KOR bound to the G protein-biased agonist nalfurafine, the first approved KOR-targeting drug. We also identify an arrestin-biased KOR agonist, WMS-X600. Using MD simulations of KOR bound to nalfurafine, WMS-X600, and a balanced agonist U50,488, we identify three active-state receptor conformations, including one that appears to favor arrestin signaling over G protein signaling and another that appears to favor G protein signaling over arrestin signaling. These results, combined with mutagenesis validation, provide a molecular explanation of how agonists achieve biased signaling at KOR.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-15)
- 국외 연구진
- 생명과학 > 구조생물 및 생물물리학
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