1xkb
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FACTOR XA COMPLEXED WITH A SYNTHETIC INHIBITOR FX-2212A,(2S)-(3'-AMIDINO-3-BIPHENYLYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID
OverviewOverview
Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged, as an alternative (to thrombin) target for drug discovery for, thromboembolic diseases. An inhibitor has been synthesized and the crystal, structure of the complex between Des[1-44] factor Xa and the inhibitor has, been determined by crystallographic methods in two different crystal forms, to 2.3- and 2.4-A resolution. The racemic mixture of inhibitor FX-2212, (2RS)-(3'-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits, factor Xa activity by 50% at 272 nM in vitro. The S-isomer of FX-2212, (FX-2212a) was found to bind to the active site of factor Xa in both, crystal forms. The biphenylamidine of FX-2212a occupies the S1-pocket, and, the pyridine ring makes hydrophobic interactions with the factor Xa, aryl-binding site. Several water molecules meditate inhibitor binding to, residues in the active site. In contrast to the earlier crystal structures, of factor Xa, such as those of apo-Des[1-45] factor Xa and Des[1-44], factor Xa in complex with a naphthyl inhibitor DX-9065a, two epidermal, growth factor-like domains of factor Xa are well ordered in both our, crystal forms as well as the region between the two domains, which, recently was found to be the binding site of the effector cell protease, receptor-1. This structure provides a basis for designing next generation, inhibitors of factor Xa.
DiseaseDisease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this StructureAbout this Structure
1XKB is a Protein complex structure of sequences from Homo sapiens with CA and 4PP as ligands. Active as Coagulation factor Xa, with EC number 3.4.21.6 Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for chemical inhibition of human blood coagulation factor Xa., Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH, Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6630-5. PMID:9618463
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