1fjs

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CRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED WITH FACTOR XA

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Factor Xa plays a critical role in the formation of blood clots. This, serine protease catalyzes the conversion of prothrombin to thrombin, the, first joint step that links the intrinsic and extrinsic coagulation, pathways. There is considerable interest in the development of factor Xa, inhibitors for the intervention in thrombic diseases. This paper presents, the structure of the inhibitor ZK-807834, also known as CI-1031, bound to, factor Xa and provides the details of the protein purification and, crystallization. Results from mass spectrometry indicate that the factor, Xa underwent autolysis during crystallization and the first EGF-like, domain was cleaved from the protein. The crystal structure of the complex, shows that the amidine of ZK-807834 forms a salt bridge with Asp189 in the, S1 pocket and the basic imidazoline fits snugly into the S4 site. The, central pyridine ring provides a fairly rigid linker between these groups., This rigidity helps minimize entropic losses during binding. In addition, the structure reveals new interactions that were not found in the previous, factor Xa/inhibitor complexes. ZK-807834 forms a strong hydrogen bond, between an ionized 2-hydroxy group and Ser195 of factor Xa. There is also, an aromatic ring-stacking interaction between the inhibitor and Trp215 in, the S4 pocket. These interactions contribute to both the potency of this, compound (K(I) = 0.11 nM) and the >2500-fold selectivity against, homologous serine proteases such as trypsin.

Disease

Known disease associated with this structure: Factor X deficiency OMIM:[227600]

About this Structure

1FJS is a Protein complex structure of sequences from Homo sapiens with CA, CL, Z34 and GOL as ligands. Active as Coagulation factor Xa, with EC number 3.4.21.6 Full crystallographic information is available from OCA.

Reference

Preparation, characterization, and the crystal structure of the inhibitor ZK-807834 (CI-1031) complexed with factor Xa., Adler M, Davey DD, Phillips GB, Kim SH, Jancarik J, Rumennik G, Light DR, Whitlow M, Biochemistry. 2000 Oct 17;39(41):12534-42. PMID:11027132

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