首页 | 本学科首页   官方微博 | 高级检索  
   检索      


Structural Insights into the Unique Modes of Relaxin-Binding and Tethered-Agonist Mediated Activation of RXFP1 and RXFP2
Institution:1. Department of Biochemistry & Pharmacology, The University of Melbourne, Parkville, Victoria 3052, Australia;2. Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia;3. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria 3052, Australia;4. Australian Nuclear Science Technology Organisation, The Australian Synchrotron, 800 Blackburn Rd, Clayton, Victoria 3168, Australia;5. School of Chemistry, The University of Melbourne, Parkville, Victoria 3052, Australia;1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel;2. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel;3. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel;1. Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON L8S 4M1, Canada;2. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4M1, Canada;1. KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Bacteriology, B-3000 Leuven, Belgium;2. Centre for Structural Systems Biology (CSSB), Notkestrasse 85, D-22607 Hamburg, Germany;3. University Medical Center Hamburg-Eppendorf (UKE), Institute for Structural and Systems Biology, Notkestrasse 85, D-22607 Hamburg, Germany;4. German Electron Synchrotron Centre (DESY), Notkestrasse 85, D-22607 Hamburg, Germany;5. Molecular Microscopy Research Group, Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG Groningen, the Netherlands;6. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Life Sciences Institute, University of British Columbia, Vancouver, Canada;7. Department of Structural Biology, St. Jude Children’s Research Hospital, 263 Danny Thomas Place, Memphis, TN 38105, United States;8. Physical and Synthetic Biology, Faculty of Biology, Ludwig Maximilians-Universität München, Großhadernerstr. 2-4, 82152 Planegg-Martinsried, Germany;1. Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada;2. Institut de Recherche en Immunologie et Cancérologie (IRIC) and Département de biochimie et de médecine moléculaire, Faculté de médecine, Université de Montréal, Montréal, QC, Canada;1. Department of Internal Medicine III, Cardiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany;2. DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Germany;3. Center for Translational Medicine, Jefferson University, Philadelphia, PA 19107, USA;4. CMCP-Center for Model System and Comparative Pathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany;5. Division of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany;1. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA;2. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA;3. Biology Department, Morosky College of Health Professions and Sciences, Gannon University, Erie, PA, USA;4. Research Service, VA Nebraska-Western Iowa Health Care System, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA;5. Research Service, VA Nebraska-Western Iowa Health Care System, Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA;6. Cardiovascular Disease Theme, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, VIC, Australia;7. Central Clinical School, Monash University, Prahran, VIC, Australia
Abstract:Our poor understanding of the mechanism by which the peptide-hormone H2 relaxin activates its G protein coupled receptor, RXFP1 and the related receptor RXFP2, has hindered progress in its therapeutic development. Both receptors possess large ectodomains, which bind H2 relaxin, and contain an N-terminal LDLa module that is essential for receptor signaling and postulated to be a tethered agonist. Here, we show that a conserved motif (GDxxGWxxxF), C-terminal to the LDLa module, is critical for receptor activity. Importantly, this motif adopts different structures in RXFP1 and RXFP2, suggesting distinct activation mechanisms. For RXFP1, the motif is flexible, weakly associates with the LDLa module, and requires H2 relaxin binding to stabilize an active conformation. Conversely, the GDxxGWxxxF motif in RXFP2 is more closely associated with the LDLa module, forming an essential binding interface for H2 relaxin. These differences in the activation mechanism will aid drug development targeting these receptors.
Keywords:G protein-coupled receptor  solution NMR  peptide agonist  protein conformational dynamics  peptide-protein complex  RXFP1  RXFP2"}  {"#name":"keyword"  "$":{"id":"k0035"}  "$$":[{"#name":"text"  "_":"relaxin family peptide receptor 1 and 2  LDLa"}  {"#name":"keyword"  "$":{"id":"k0045"}  "$$":[{"#name":"text"  "_":"low density lipoprotein class A  TMD"}  {"#name":"keyword"  "$":{"id":"k0055"}  "$$":[{"#name":"text"  "_":"transmembrane domain  LRR"}  {"#name":"keyword"  "$":{"id":"k0065"}  "$$":[{"#name":"text"  "_":"leucine-rich repeat  LGR"}  {"#name":"keyword"  "$":{"id":"k0075"}  "$$":[{"#name":"text"  "_":"LRR-containing GPCR  EOM"}  {"#name":"keyword"  "$":{"id":"k0085"}  "$$":[{"#name":"text"  "_":"Ensemble Optimization Method  ssRXFP1"}  {"#name":"keyword"  "$":{"id":"k0095"}  "$$":[{"#name":"text"  "_":"ssRXFP2  soluble scaffold displaying the extracellular loops-1 and -2 of RXFP1 and RXFP2  HSQC"}  {"#name":"keyword"  "$":{"id":"k0105"}  "$$":[{"#name":"text"  "_":"Heteronuclear single quantum coherence  CPMG"}  {"#name":"keyword"  "$":{"id":"k0115"}  "$$":[{"#name":"text"  "_":"Carr-Purcell-Meiboom-Gill
本文献已被 ScienceDirect 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号