Structural insights on ligand recognition at the human leukotriene B4 receptor 1
| Autor: | Vadim Cherezov, Gye Won Han, Anastasiia Sadybekov, Nairie Michaelian, Stephen M. Soisson, Jeremy Presland, Élie Besserer-Offroy, Xavier Fradera, Philippe Sarret, Vsevolod Katritch, Kerrie Spencer, Phieng Siliphaivanh, Beata Zamlynny, Petr Popov, Harini Krishnamurthy |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cell type Science Receptors Leukotriene B4 General Physics and Astronomy BLT receptor Endogeny Computational biology Spodoptera Crystallography X-Ray Ligands General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine G protein-coupled receptors Sf9 Cells Animals Humans Hypoglycemic Agents X-ray crystallography Multidisciplinary Binding Sites Chemistry Mutagenesis Chemotaxis Leukotriene B4 Receptor 1 General Chemistry Ligand (biochemistry) Recombinant Proteins 3. Good health Molecular Docking Simulation 030104 developmental biology HEK293 Cells Diabetes Mellitus Type 2 Docking (molecular) Mutagenesis Site-Directed 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| ISSN: | 2041-1723 |
| Popis: | The leukotriene B4 receptor 1 (BLT1) regulates the recruitment and chemotaxis of different cell types and plays a role in the pathophysiology of infectious, allergic, metabolic, and tumorigenic human diseases. Here we present a crystal structure of human BLT1 (hBLT1) in complex with a selective antagonist MK-D-046, developed for the treatment of type 2 diabetes and other inflammatory conditions. Comprehensive analysis of the structure and structure-activity relationship data, reinforced by site-directed mutagenesis and docking studies, reveals molecular determinants of ligand binding and selectivity toward different BLT receptor subtypes and across species. The structure helps to identify a putative membrane-buried ligand access channel as well as potential receptor binding modes of endogenous agonists. These structural insights of hBLT1 enrich our understanding of its ligand recognition and open up future avenues in structure-based drug design. Human leukotriene B4 receptors (BLT1 and BLT2) are members of the GPCR superfamily that respond to a potent pro-inflammatory lipid and chemoattractant LTB4. Here authors determined a crystal structure of the human BLT1 in complex with a selective antagonist MK-D-046 and provide insights into hBLT1 ligand recognition and its mechanism of action. |
| Databáze: | OpenAIRE |
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