PDBsum entry 1mq5

Blood clotting

PDB id: 1mq5

Contents

Protein chains

233 a.a. *

51 a.a. *

Ligands

XLC

GOL ×3

Metals

_CA

Waters ×172

* Residue conservation analysis

PDB id:

1mq5

Name:

Blood clotting

Title:

Crystal structure of 3-chloro-n-[4-chloro-2-[[(4-chlorophenyl) amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2- thiophenecarboxamide complexed with human factor xa

Structure:

Coagulation factor x heavy chain. Chain: a. Fragment: catalytic domain. Synonym: stuart factor. Coagulation factor x light chain. Chain: l. Fragment: epidermal growth factor like domain 2. Synonym: stuart factor. Ec: 3.4.21.6

Source:

Homo sapiens. Human. Organism_taxid: 9606. Other_details: extracted from blood. Other_details: extracted from blood

Biol. unit:

Dimer (from PQS)

Resolution:

2.10Å R-factor: 0.190 R-free: 0.264

Authors:

M.Adler,M.Whitlow

Key ref:

M.Adler et al. (2002). Crystal structures of two potent nonamidine inhibitors bound to factor Xa. Biochemistry, 41, 15514-15523. PubMed id: 12501180 DOI: 10.1021/bi0264061

Date:

13-Sep-02 Release date: 28-Jan-03

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 233 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 51 a.a.

Enzyme reactions

• Enzyme class: Chains A, L: E.C.3.4.21.6 - coagulation factor Xa.
• Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

DOI no: 10.1021/bi0264061

Biochemistry 41:15514-15523 (2002)

PubMed id: 12501180

Crystal structures of two potent nonamidine inhibitors bound to factor Xa.

M.Adler, M.J.Kochanny, B.Ye, G.Rumennik, D.R.Light, S.Biancalana, M.Whitlow.

ABSTRACT

There has been intense interest in the development of factor Xa inhibitors for the treatment of thrombotic diseases. Our laboratory has developed a series of novel non-amidine inhibitors of factor Xa. This paper presents two crystal structures of compounds from this series bound to factor Xa. The first structure is derived from the complex formed between factor Xa and compound 1. Compound 1 was the first non-amidine factor Xa inhibitor from our lab that had measurable potency in an in vitro assay of anticoagulant activity. The second compound, 2, has a molar affinity for factor Xa (K(iapp)) of 7 pM and good bioavailability. The two inhibitors bind in an L-shaped conformation with a chloroaromatic ring buried deeply in the S1 pocket. The opposite end of these compounds contains a basic substituent that extends into the S4 binding site. A chlorinated phenyl ring bridges the substituents in the S1 and S4 pockets via amide linkers. The overall conformation is similar to the previously published structures for amidine-based inhibitors complexed with factor Xa. However, there are significant differences in the interactions between the inhibitor and the protein at the atomic level. Most notably, there is no group that forms a salt bridge with the carboxylic acid at the base of the S1 pocket (Asp189). Each inhibitor forms only one well-defined hydrogen bond to the protein. There are no direct charge-charge interactions. The results indicate that electrostatic interactions play a secondary role in the binding of these potent inhibitors.