PDBsum entry 2ra0

Hydrolase

PDB id: 2ra0

Contents

Protein chains

234 a.a. *

51 a.a. *

Ligands

JNJ

Waters ×81

* Residue conservation analysis

PDB id:

2ra0

Name:

Hydrolase

Title:

X-ray structure of fxa in complex with 7-fluoroindazole

Structure:

Coagulation factor x. Chain: a. Fragment: heavy chain, unp residues 235-468. Synonym: stuart factor, stuart-prower factor. Engineered: yes. Coagulation factor x. Chain: l. Fragment: light chain, unp residues 128-178. Synonym: stuart factor, stuart-prower factor.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f10. Other_details: mammalian. Other_details: mammalian

Resolution:

2.30Å R-factor: 0.246 R-free: 0.314

Authors:

M.C.Abad

Key ref:

Y.K.Lee et al. (2008). 7-fluoroindazoles as potent and selective inhibitors of factor Xa. J Med Chem, 51, 282-297. PubMed id: 18159923

Date:

14-Sep-07 Release date: 29-Jan-08

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 234 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 51 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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.

J Med Chem 51:282-297 (2008)

PubMed id: 18159923

7-fluoroindazoles as potent and selective inhibitors of factor Xa.

Y.K.Lee, D.J.Parks, T.Lu, T.V.Thieu, T.Markotan, W.Pan, D.F.McComsey, K.L.Milkiewicz, C.S.Crysler, N.Ninan, M.C.Abad, E.C.Giardino, B.E.Maryanoff, B.P.Damiano, M.R.Player.

ABSTRACT

We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.