5lxa

CRYSTAL STRUCTURE OF HUMAN ADIPONECTIN RECEPTOR 2 IN COMPLEX WITH A C18 FREE FATTY ACID AT 3.0 ANGSTROM RESOLUTIONCRYSTAL STRUCTURE OF HUMAN ADIPONECTIN RECEPTOR 2 IN COMPLEX WITH A C18 FREE FATTY ACID AT 3.0 ANGSTROM RESOLUTION

Structural highlights

5lxa is a 2 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PAQR2_HUMAN Receptor for ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism (PubMed:12802337, PubMed:25855295). Required for normal body fat and glucose homeostasis. ADIPOQ-binding activates a signaling cascade that leads to increased PPARA activity, and ultimately to increased fatty acid oxidation and glucose uptake. Has intermediate affinity for globular and full-length adiponectin. Required for normal revascularization after chronic ischemia caused by severing of blood vessels (By similarity).[UniProtKB:Q8BQS5]^[1] ^[2]

Publication Abstract from PubMed

Adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid (FFA). The crystal structures of the two receptor subtypes, ADIPOR1 and ADIPOR2, show a similar overall seven-transmembrane-domain architecture with large unoccupied cavities and a zinc binding site within the seven transmembrane domain. However, the molecular mechanisms by which ADIPORs function are not known. Here we describe the crystal structure of ADIPOR2 bound to a FFA molecule and show that ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin. We also identify a ceramide binding pose and propose a possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearrange quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Furthermore, we present a revised ADIPOR1 crystal structure exhibiting a seven-transmembrane-domain architecture that is clearly distinct from that of ADIPOR2. In this structure, no FFA is observed and the ceramide binding pocket and putative zinc catalytic site are exposed to the inner membrane leaflet. ADIPOR1 also possesses intrinsic ceramidase activity, so we suspect that the two distinct structures may represent key steps in the enzymatic activity of ADIPORs. The ceramidase activity is low, however, and further studies will be required to characterize fully the enzymatic parameters and substrate specificity of ADIPORs. These insights into ADIPOR function will enable the structure-based design of potent modulators of these clinically relevant enzymes.

Structural insights into adiponectin receptors suggest ceramidase activity.,Vasiliauskaite-Brooks I, Sounier R, Rochaix P, Bellot G, Fortier M, Hoh F, De Colibus L, Bechara C, Saied EM, Arenz C, Leyrat C, Granier S Nature. 2017 Mar 22. doi: 10.1038/nature21714. PMID:28329765^[3]

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

References

↑ Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003 Jun 12;423(6941):762-9. PMID:12802337 doi:http://dx.doi.org/10.1038/nature01705
↑ Tanabe H, Fujii Y, Okada-Iwabu M, Iwabu M, Nakamura Y, Hosaka T, Motoyama K, Ikeda M, Wakiyama M, Terada T, Ohsawa N, Hato M, Ogasawara S, Hino T, Murata T, Iwata S, Hirata K, Kawano Y, Yamamoto M, Kimura-Someya T, Shirouzu M, Yamauchi T, Kadowaki T, Yokoyama S. Crystal structures of the human adiponectin receptors. Nature. 2015 Apr 16;520(7547):312-6. doi: 10.1038/nature14301. Epub 2015 Apr 8. PMID:25855295 doi:http://dx.doi.org/10.1038/nature14301
↑ Vasiliauskaite-Brooks I, Sounier R, Rochaix P, Bellot G, Fortier M, Hoh F, De Colibus L, Bechara C, Saied EM, Arenz C, Leyrat C, Granier S. Structural insights into adiponectin receptors suggest ceramidase activity. Nature. 2017 Mar 22. doi: 10.1038/nature21714. PMID:28329765 doi:http://dx.doi.org/10.1038/nature21714

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OCA

[1] Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003 Jun 12;423(6941):762-9. PMID:12802337 doi:http://dx.doi.org/10.1038/nature01705

[2] Tanabe H, Fujii Y, Okada-Iwabu M, Iwabu M, Nakamura Y, Hosaka T, Motoyama K, Ikeda M, Wakiyama M, Terada T, Ohsawa N, Hato M, Ogasawara S, Hino T, Murata T, Iwata S, Hirata K, Kawano Y, Yamamoto M, Kimura-Someya T, Shirouzu M, Yamauchi T, Kadowaki T, Yokoyama S. Crystal structures of the human adiponectin receptors. Nature. 2015 Apr 16;520(7547):312-6. doi: 10.1038/nature14301. Epub 2015 Apr 8. PMID:25855295 doi:http://dx.doi.org/10.1038/nature14301

[3] Vasiliauskaite-Brooks I, Sounier R, Rochaix P, Bellot G, Fortier M, Hoh F, De Colibus L, Bechara C, Saied EM, Arenz C, Leyrat C, Granier S. Structural insights into adiponectin receptors suggest ceramidase activity. Nature. 2017 Mar 22. doi: 10.1038/nature21714. PMID:28329765 doi:http://dx.doi.org/10.1038/nature21714

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