7v62 | pdb_00007v62
Crystal structure of human OSBP ORD in complex with cholesterol
Structural highlights
FunctionOSBP1_HUMAN Binds cholesterol and a range of oxysterols. Cholesterol binding promotes the formation of a complex with PP2A and a tyrosine phosphatase which dephosphorylate ERK1/2, whereas 25-hydroxycholesterol causes its disassembly. Regulates cholesterol efflux by decreasing ABCA1 stability.[1] [2] Publication Abstract from PubMedOxysterol-binding protein (OSBP), which transports cholesterol and phosphatidylinositol 4-monophosphate (PtdIns[4]P) between different organelles, serves as a conserved host factor for the replication of various viruses, and OSBP inhibitors exhibit antiviral effects. Here, we determined the crystal structure of the lipid transfer domain of human OSBP in complex with endogenous cholesterol. The hydrocarbon tail and tetracyclic ring of cholesterol interact with the hydrophobic tunnel of OSBP, and the hydroxyl group of cholesterol forms a hydrogen bond network at the bottom of the tunnel. Systematic mutagenesis of the ligand-binding region revealed that M446W and L590W substitutions confer functional tolerance to an OSBP inhibitor, T-00127-HEV2. Employing the M446W variant as a functional replacement for the endogenous OSBP in the presence of T-00127-HEV2, we have identified previously unappreciated amino acid residues required for viral replication. The combined use of the inhibitor and the OSBP variant will be useful in elucidating the enigmatic in vivo functions of OSBP. Ligand Recognition by the Lipid Transfer Domain of Human OSBP Is Important for Enterovirus Replication.,Kobayashi J, Arita M, Sakai S, Kojima H, Senda M, Senda T, Hanada K, Kato R ACS Infect Dis. 2022 May 25. doi: 10.1021/acsinfecdis.2c00108. PMID:35613096[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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