Structure and protein design of a human platelet function inhibitor
- PMID: 15006348
- DOI: 10.1016/s0092-8674(04)00172-2
Structure and protein design of a human platelet function inhibitor
Erratum in
- Cell. 2004 Apr 30;117(3):413
Abstract
Hematophagous arthropods secrete a salivary apyrase that inhibits platelet activation by catabolizing ADP released from damaged tissues and blood cells. We report the X-ray crystal structures of a human enzyme of the soluble apyrase family in its apo state and bound to a substrate analog. The structures reveal a nucleotide binding domain comprising a five-blade beta propeller, binding determinants of the substrate and the active site, and an unusual calcium binding site with a potential regulatory function. Using a comparative structural biology approach, we were able to redesign the human apyrase so as to enhance its ADPase activity by more than 100-fold. The engineered enzyme is a potent inhibitor of platelet aggregation and may serve as the basis for the development of a new class of antithrombotic agents.
Similar articles
-
Apyrase activity and adenosine diphosphate induced platelet aggregation inhibition by the salivary gland proteins of Culicoides variipennis, the North American vector of bluetongue viruses.Vet Parasitol. 1996 Feb;61(3-4):327-38. doi: 10.1016/0304-4017(95)00828-4. Vet Parasitol. 1996. PMID: 8720570
-
Cloning, expression, and characterization of a soluble calcium-activated nucleotidase, a human enzyme belonging to a new family of extracellular nucleotidases.Arch Biochem Biophys. 2002 Oct 1;406(1):105-15. doi: 10.1016/s0003-9861(02)00420-4. Arch Biochem Biophys. 2002. PMID: 12234496
-
Expression of functional recombinant mosquito salivary apyrase: a potential therapeutic platelet aggregation inhibitor.Platelets. 2006 May;17(3):178-84. doi: 10.1080/09537100500460234. Platelets. 2006. PMID: 16702045
-
Platelet aggregation inhibitors from hematophagous animals.Toxicon. 2010 Dec 15;56(7):1130-44. doi: 10.1016/j.toxicon.2009.12.003. Epub 2009 Dec 24. Toxicon. 2010. PMID: 20035779 Free PMC article. Review.
-
Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases.J Pharmacol Exp Ther. 2003 Apr;305(1):9-16. doi: 10.1124/jpet.102.043729. J Pharmacol Exp Ther. 2003. PMID: 12649347 Review.
Cited by
-
The creation of an antithrombotic surface by apyrase immobilization.Biomaterials. 2010 Jun;31(16):4484-91. doi: 10.1016/j.biomaterials.2010.02.036. Epub 2010 Mar 7. Biomaterials. 2010. PMID: 20211488 Free PMC article.
-
Cloning, expression, and characterization of salivary apyrase from Aedes albopictus.Parasitol Res. 2012 Feb;110(2):931-7. doi: 10.1007/s00436-011-2579-x. Epub 2011 Aug 14. Parasitol Res. 2012. PMID: 21842387
-
Functional characterization of a salivary apyrase from the sand fly, Phlebotomus duboscqi, a vector of Leishmania major.J Insect Physiol. 2009 Nov;55(11):1044-9. doi: 10.1016/j.jinsphys.2009.07.010. Epub 2009 Aug 11. J Insect Physiol. 2009. PMID: 19651132 Free PMC article.
-
Characterization and importance of the dimer interface of human calcium-activated nucleotidase.Biochemistry. 2008 Jan 15;47(2):771-8. doi: 10.1021/bi701578m. Epub 2007 Dec 8. Biochemistry. 2008. PMID: 18067325 Free PMC article.
-
MED resulting from recessively inherited mutations in the gene encoding calcium-activated nucleotidase CANT1.Am J Med Genet A. 2017 Sep;173(9):2415-2421. doi: 10.1002/ajmg.a.38349. Epub 2017 Jul 25. Am J Med Genet A. 2017. PMID: 28742282 Free PMC article.
Publication types
MeSH terms
Substances
Associated data
- Actions
- Actions
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
