1XKB

FACTOR XA COMPLEXED WITH A SYNTHETIC INHIBITOR FX-2212A,(2S)-(3'-AMIDINO-3-BIPHENYLYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID

Summary for 1XKB

• Entry DOI: 10.2210/pdb1xkb/pdb
• Descriptor: BLOOD COAGULATION FACTOR XA, CALCIUM ION, (2S)-(3'-AMIDINO-3-BIPHENYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID, ... (5 entities in total)
• Functional Keywords: blood coagulation factor, serine proteinase, epidermal growth factor like domain
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 4
• Total formula weight: 74878.83

Authors

Kamata, K.,Kim, S.H. (deposition date: 1998-03-19, release date: 1999-03-23, Last modification date: 2024-11-20)

Primary citation

Kamata, K.,Kawamoto, H.,Honma, T.,Iwama, T.,Kim, S.H.
Structural basis for chemical inhibition of human blood coagulation factor Xa.
Proc.Natl.Acad.Sci.USA, 95:6630-6635, 1998

PubMed Abstract: 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.

PubMed: 9618463
DOI: 10.1073/pnas.95.12.6630

Experimental method

X-RAY DIFFRACTION (2.4 Å)