Publication Date:
2012-10-23
Description:
CXCR1 is one of two high-affinity receptors for the CXC chemokine interleukin-8 (IL-8), a major mediator of immune and inflammatory responses implicated in many disorders, including tumour growth. IL-8, released in response to inflammatory stimuli, binds to the extracellular side of CXCR1. The ligand-activated intracellular signalling pathways result in neutrophil migration to the site of inflammation. CXCR1 is a class A, rhodopsin-like G-protein-coupled receptor (GPCR), the largest class of integral membrane proteins responsible for cellular signal transduction and targeted as drug receptors. Despite its importance, the molecular mechanism of CXCR1 signal transduction is poorly understood owing to the limited structural information available. Recent structural determination of GPCRs has advanced by modifying the receptors with stabilizing mutations, insertion of the protein T4 lysozyme and truncations of their amino acid sequences, as well as addition of stabilizing antibodies and small molecules that facilitate crystallization in cubic phase monoolein mixtures. The intracellular loops of GPCRs are crucial for G-protein interactions, and activation of CXCR1 involves both amino-terminal residues and extracellular loops. Our previous nuclear magnetic resonance studies indicate that IL-8 binding to the N-terminal residues is mediated by the membrane, underscoring the importance of the phospholipid bilayer for physiological activity. Here we report the three-dimensional structure of human CXCR1 determined by NMR spectroscopy. The receptor is in liquid crystalline phospholipid bilayers, without modification of its amino acid sequence and under physiological conditions. Features important for intracellular G-protein activation and signal transduction are revealed. The structure of human CXCR1 in a lipid bilayer should help to facilitate the discovery of new compounds that interact with GPCRs and combat diseases such as breast cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700570/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3700570/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Sang Ho -- Das, Bibhuti B -- Casagrande, Fabio -- Tian, Ye -- Nothnagel, Henry J -- Chu, Mignon -- Kiefer, Hans -- Maier, Klaus -- De Angelis, Anna A -- Marassi, Francesca M -- Opella, Stanley J -- P01 AI074805/AI/NIAID NIH HHS/ -- P01AI074805/AI/NIAID NIH HHS/ -- P41 EB002031/EB/NIBIB NIH HHS/ -- P41EB002031/EB/NIBIB NIH HHS/ -- R01 EB005161/EB/NIBIB NIH HHS/ -- R01 GM099986/GM/NIGMS NIH HHS/ -- R01EB005161/EB/NIBIB NIH HHS/ -- R01GM075877/GM/NIGMS NIH HHS/ -- R21GM075917/GM/NIGMS NIH HHS/ -- R21GM94727/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 29;491(7426):779-83. doi: 10.1038/nature11580. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0307, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086146" target="_blank"〉PubMed〈/a〉
Keywords:
Disulfides/chemistry/metabolism
;
Enzyme Activation
;
Heterotrimeric GTP-Binding Proteins/metabolism
;
Humans
;
Interleukin-8/chemistry/metabolism
;
Lipid Bilayers/chemistry/*metabolism
;
Models, Molecular
;
Molecular Conformation
;
Nuclear Magnetic Resonance, Biomolecular
;
Phospholipids/chemistry/*metabolism
;
Receptors, Interleukin-8A/*chemistry/*metabolism
;
Signal Transduction
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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