5zkp

Crystal structure of the human platelet-activating factor receptor in complex with SR 27417Crystal structure of the human platelet-activating factor receptor in complex with SR 27417

Structural highlights

5zkp is a 1 chain structure with sequence from Desulfovibrio vulgaris str. Hildenborough and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.81Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PTAFR_HUMAN Receptor for platelet activating factor, a chemotactic phospholipid mediator that possesses potent inflammatory, smooth-muscle contractile and hypotensive activity. Seems to mediate its action via a G protein that activates a phosphatidylinositol-calcium second messenger system.^[1] ^[2] ^[3] ^[4] FLAV_NITV2 Low-potential electron donor to a number of redox enzymes.

Publication Abstract from PubMed

Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here we report crystal structures of human PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491 at 2.8-A and 2.9-A resolution, respectively. The structures, supported by molecular docking of PAF, provide insights into the signal-recognition mechanisms of PAFR. The PAFR-SR 27417 structure reveals an unusual conformation showing that the intracellular tips of helices II and IV shift outward by 13 A and 4 A, respectively, and helix VIII adopts an inward conformation. The PAFR structures, combined with single-molecule FRET and cell-based functional assays, suggest that the conformational change in the helical bundle is ligand dependent and plays a critical role in PAFR activation, thus greatly extending knowledge about signaling by G-protein-coupled receptors.

Structural basis for signal recognition and transduction by platelet-activating-factor receptor.,Cao C, Tan Q, Xu C, He L, Yang L, Zhou Y, Zhou Y, Qiao A, Lu M, Yi C, Han GW, Wang X, Li X, Yang H, Rao Z, Jiang H, Zhao Y, Liu J, Stevens RC, Zhao Q, Zhang XC, Wu B Nat Struct Mol Biol. 2018 Jun;25(6):488-495. doi: 10.1038/s41594-018-0068-y. Epub, 2018 May 28. PMID:29808000^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sugimoto T, Tsuchimochi H, McGregor CG, Mutoh H, Shimizu T, Kurachi Y. Molecular cloning and characterization of the platelet-activating factor receptor gene expressed in the human heart. Biochem Biophys Res Commun. 1992 Dec 15;189(2):617-24. PMID:1281995
↑ Kunz D, Gerard NP, Gerard C. The human leukocyte platelet-activating factor receptor. cDNA cloning, cell surface expression, and construction of a novel epitope-bearing analog. J Biol Chem. 1992 May 5;267(13):9101-6. PMID:1374385
↑ Ye RD, Prossnitz ER, Zou AH, Cochrane CG. Characterization of a human cDNA that encodes a functional receptor for platelet activating factor. Biochem Biophys Res Commun. 1991 Oct 15;180(1):105-11. PMID:1656963
↑ Nakamura M, Honda Z, Izumi T, Sakanaka C, Mutoh H, Minami M, Bito H, Seyama Y, Matsumoto T, Noma M, et al.. Molecular cloning and expression of platelet-activating factor receptor from human leukocytes. J Biol Chem. 1991 Oct 25;266(30):20400-5. PMID:1657923
↑ Cao C, Tan Q, Xu C, He L, Yang L, Zhou Y, Zhou Y, Qiao A, Lu M, Yi C, Han GW, Wang X, Li X, Yang H, Rao Z, Jiang H, Zhao Y, Liu J, Stevens RC, Zhao Q, Zhang XC, Wu B. Structural basis for signal recognition and transduction by platelet-activating-factor receptor. Nat Struct Mol Biol. 2018 Jun;25(6):488-495. doi: 10.1038/s41594-018-0068-y. Epub, 2018 May 28. PMID:29808000 doi:http://dx.doi.org/10.1038/s41594-018-0068-y

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OCA

[1] Sugimoto T, Tsuchimochi H, McGregor CG, Mutoh H, Shimizu T, Kurachi Y. Molecular cloning and characterization of the platelet-activating factor receptor gene expressed in the human heart. Biochem Biophys Res Commun. 1992 Dec 15;189(2):617-24. PMID:1281995

[2] Kunz D, Gerard NP, Gerard C. The human leukocyte platelet-activating factor receptor. cDNA cloning, cell surface expression, and construction of a novel epitope-bearing analog. J Biol Chem. 1992 May 5;267(13):9101-6. PMID:1374385

[3] Ye RD, Prossnitz ER, Zou AH, Cochrane CG. Characterization of a human cDNA that encodes a functional receptor for platelet activating factor. Biochem Biophys Res Commun. 1991 Oct 15;180(1):105-11. PMID:1656963

[4] Nakamura M, Honda Z, Izumi T, Sakanaka C, Mutoh H, Minami M, Bito H, Seyama Y, Matsumoto T, Noma M, et al.. Molecular cloning and expression of platelet-activating factor receptor from human leukocytes. J Biol Chem. 1991 Oct 25;266(30):20400-5. PMID:1657923

[5] Cao C, Tan Q, Xu C, He L, Yang L, Zhou Y, Zhou Y, Qiao A, Lu M, Yi C, Han GW, Wang X, Li X, Yang H, Rao Z, Jiang H, Zhao Y, Liu J, Stevens RC, Zhao Q, Zhang XC, Wu B. Structural basis for signal recognition and transduction by platelet-activating-factor receptor. Nat Struct Mol Biol. 2018 Jun;25(6):488-495. doi: 10.1038/s41594-018-0068-y. Epub, 2018 May 28. PMID:29808000 doi:http://dx.doi.org/10.1038/s41594-018-0068-y

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