PDBsum entry 3ens

Hydrolase, blood clotting

PDB id: 3ens

Contents

Protein chains

84 a.a. *

238 a.a. *

84 a.a. *

Ligands

GOL ×7

ENS ×2

MES ×2

ACT ×2

Metals

_CA ×2

_NA ×2

Waters ×304

* Residue conservation analysis

PDB id:

3ens

Name:

Hydrolase, blood clotting

Title:

Crystal structure of human fxa in complex with methyl (2z)-3-[(3- chloro-1h-indol-7-yl)amino]-2-cyano-3-{[(3s)-2-oxo-1-(2-oxo-2- pyrrolidin-1-ylethyl)azepan-3-yl]amino}acrylate

Structure:

Factor x light chain. Chain: a, c. Fragment: sequence database residues 93-178. Activated factor xa heavy chain. Chain: b, d. Fragment: sequence database residues 235-472. Ec: 3.4.21.6

Source:

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

Resolution:

2.30Å R-factor: 0.225 R-free: 0.286

Authors:

H.E.Klei

Key ref:

Y.Shi et al. (2008). Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-chloroindole-7-yl-based factor Xa inhibitors. J Med Chem, 51, 7541-7551. PubMed id: 18998662

Date:

25-Sep-08 Release date: 30-Dec-08

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 84 a.a.*

Protein chains

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 238 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 84 a.a.

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

Enzyme reactions

• Enzyme class: Chains A, B, C, D: 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 51:7541-7551 (2008)

PubMed id: 18998662

Design, structure-activity relationships, X-ray crystal structure, and energetic contributions of a critical P1 pharmacophore: 3-chloroindole-7-yl-based factor Xa inhibitors.

Y.Shi, D.Sitkoff, J.Zhang, H.E.Klei, K.Kish, E.C.Liu, K.S.Hartl, S.M.Seiler, M.Chang, C.Huang, S.Youssef, T.E.Steinbacher, W.A.Schumacher, N.Grazier, A.Pudzianowski, A.Apedo, L.Discenza, J.Yanchunas, P.D.Stein, K.S.Atwal.

ABSTRACT

An indole-based P1 moiety was incorporated into a previously established factor Xa inhibitor series. The indole group was designed to hydrogen-bond with the carbonyl of Gly218, while its 3-methyl or 3-chloro substituent was intended to interact with Tyr228. These interactions were subsequently observed in the X-ray crystal structure of compound 18. SAR studies led to the identification of compound 20 as the most potent FXa inhibitor in this series (IC(50) = 2.4 nM, EC(2xPT) = 1.2 microM). An in-depth energetic analysis suggests that the increased binding energy of 3-chloroindole-versus 3-methylindole-containing compounds in this series is due primarily to (a) the more hydrophobic nature of chloro- versus methyl-containing compounds and (b) an increased interaction of 3-chloroindole versus 3-methylindole with Gly218 backbone. The stronger hydrophobicity of chloro- versus methyl-substituted aromatics may partly explain the general preference for chloro- versus methyl-substituted P1 groups in FXa, which extends beyond the current series.