5inh

Crystal structure of Autotaxin/ENPP2 with a covalent fragmentCrystal structure of Autotaxin/ENPP2 with a covalent fragment

Structural highlights

5inh is a 1 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.84Å
Ligands:	, , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ENPP2_MOUSE Note=May contribute to obesity.

Function

ENPP2_MOUSE Hydrolyzes lysophospholipids to produce lysophosphatidic acid (LPA) in extracellular fluids. Major substrate is lysophosphatidylcholine. Also can act on sphingosylphosphphorylcholine producing sphingosine-1-phosphate, a modulator of cell motility. Can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, and barely ATP. Involved in several motility-related processes such as angiogenesis and neurite outgrowth. Acts as an angiogenic factor by stimulating migration of smooth muscle cells and microtubule formation. Stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein. May have a role in induction of parturition. Possible involvement in cell proliferation and adipose tissue development. Tumor cell motility-stimulating factor.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Serine hydrolases are susceptible to potent reversible inhibition by boronic acids. Large collections of chemically diverse boronic acid fragments are commercially available because of their utility in coupling chemistry. We repurposed the approximately 650 boronic acid reagents in our collection as a directed fragment library targeting serine hydrolases and related enzymes. Highly efficient hits (LE > 0.6) often result. The utility of the approach is illustrated with the results against autotaxin, a phospholipase implicated in cardiovascular disease.

Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes.,Lanier M, Cole DC, Istratiy Y, Klein MG, Schwartz PA, Tjhen R, Jennings A, Hixon MS J Med Chem. 2017 Jun 22;60(12):5209-5215. doi: 10.1021/acs.jmedchem.6b01224. Epub, 2017 Jun 9. PMID:28564542^[4]

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

References

↑ Boucher J, Quilliot D, Praderes JP, Simon MF, Gres S, Guigne C, Prevot D, Ferry G, Boutin JA, Carpene C, Valet P, Saulnier-Blache JS. Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Diabetologia. 2005 Mar;48(3):569-77. Epub 2005 Feb 8. PMID:15700135 doi:10.1007/s00125-004-1660-8
↑ Pradere JP, Tarnus E, Gres S, Valet P, Saulnier-Blache JS. Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase. Biochim Biophys Acta. 2007 Jan;1771(1):93-102. Epub 2006 Dec 6. PMID:17208043 doi:10.1016/j.bbalip.2006.11.010
↑ Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat Struct Mol Biol. 2011 Feb;18(2):205-12. doi: 10.1038/nsmb.1998. Epub 2011 Jan, 16. PMID:21240269 doi:10.1038/nsmb.1998
↑ Lanier M, Cole DC, Istratiy Y, Klein MG, Schwartz PA, Tjhen R, Jennings A, Hixon MS. Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes. J Med Chem. 2017 Jun 22;60(12):5209-5215. doi: 10.1021/acs.jmedchem.6b01224. Epub, 2017 Jun 9. PMID:28564542 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01224

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OCA

[1] Boucher J, Quilliot D, Praderes JP, Simon MF, Gres S, Guigne C, Prevot D, Ferry G, Boutin JA, Carpene C, Valet P, Saulnier-Blache JS. Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression. Diabetologia. 2005 Mar;48(3):569-77. Epub 2005 Feb 8. PMID:15700135 doi:10.1007/s00125-004-1660-8

[2] Pradere JP, Tarnus E, Gres S, Valet P, Saulnier-Blache JS. Secretion and lysophospholipase D activity of autotaxin by adipocytes are controlled by N-glycosylation and signal peptidase. Biochim Biophys Acta. 2007 Jan;1771(1):93-102. Epub 2006 Dec 6. PMID:17208043 doi:10.1016/j.bbalip.2006.11.010

[3] Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat Struct Mol Biol. 2011 Feb;18(2):205-12. doi: 10.1038/nsmb.1998. Epub 2011 Jan, 16. PMID:21240269 doi:10.1038/nsmb.1998

[4] Lanier M, Cole DC, Istratiy Y, Klein MG, Schwartz PA, Tjhen R, Jennings A, Hixon MS. Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes. J Med Chem. 2017 Jun 22;60(12):5209-5215. doi: 10.1021/acs.jmedchem.6b01224. Epub, 2017 Jun 9. PMID:28564542 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01224

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