Structure of the chemokine receptor CXCR1 in phospholipid bilayers
| Autor: | Stanley J. Opella, Henry J. Nothnagel, Bibhuti B. Das, Anna A. De Angelis, Mignon Chu, Fabio Casagrande, Hans Kiefer, Sang Ho Park, Ye Tian, Francesca M. Marassi, Klaus Maier |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Lipid Bilayers Molecular Conformation Phospholipid Biology 010402 general chemistry 01 natural sciences Receptors Interleukin-8A 03 medical and health sciences Chemokine receptor chemistry.chemical_compound Humans Disulfides Lipid bilayer Receptor Nuclear Magnetic Resonance Biomolecular Integral membrane protein Phospholipids 030304 developmental biology G protein-coupled receptor 0303 health sciences Multidisciplinary Interleukin-8 Heterotrimeric GTP-Binding Proteins 0104 chemical sciences 3. Good health Cell biology Enzyme Activation chemistry Signal transduction Intracellular Signal Transduction |
| Zdroj: | Nature. 491:779-783 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature11580 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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