2BQ7

Crystal structure of factor Xa in complex with 43

Summary for 2BQ7

• Entry DOI: 10.2210/pdb2bq7/pdb
• Related: 1C5M 1EZQ 1F0R 1F0S 1FAX 1FJS 1FXY 1G2L 1G2M 1HCG 1IOE 1IQE 1IQF 1IQG 1IQH 1IQI 1IQJ 1IQK 1IQL 1IQM 1IQN 1KSN 1KYE 1LPG 1LPK 1LPZ 1LQD 1MQ5 1MQ6 1MSX 1NFU 1NFW 1NFX 1NFY 1NL8 1P0S 1V3X 1XKA 1XKB 2BMG 2BOH 2BOK 2BQ6 2BQW
• Descriptor: COAGULATION FACTOR X, FACTOR XA, N-(1-ISOPROPYLPIPERIDIN-4-YL)-1-(3-METHOXYBENZYL)-1H-INDOLE-2-CARBOXAMIDE, ... (5 entities in total)
• Functional Keywords: blood coagulation, blood coagulation factor, calcium-binding, egf-like domain, gamma-carboxyglutamic acid, glycoprotein, hydrolase, hydroxylation, plasma, polymorphism, protein inhibitor complex, serine proteinase, serine protease, vitamin k, zymogen
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 34283.89

Authors

Nazare, M.,Will, D.W.,Matter, H.,Schreuder, H.,Ritter, K.,Urmann, M.,Essrich, M.,Bauer, A.,Wagner, M.,Czech, J.,Laux, V.,Wehner, V. (deposition date: 2005-04-27, release date: 2006-04-26, Last modification date: 2024-10-16)

Primary citation

Nazare, M.,Will, D.W.,Matter, H.,Schreuder, H.,Ritter, K.,Urmann, M.,Essrich, M.,Bauer, A.,Wagner, M.,Czech, J.,Lorenz, M.,Laux, V.,Wehner, V.
Probing the Subpockets of Factor Xa Reveals Two Binding Modes for Inhibitors Based on a 2-Carboxyindole Scaffold: A Study Combining Structure-Activity Relationship and X-Ray Crystallography.
J.Med.Chem., 48:4511-, 2005

PubMed Abstract: Structure-activity relationships within a series of highly potent 2-carboxyindole-based factor Xa inhibitors incorporating a neutral P1 ligand are described with particular emphasis on the structural requirements for addressing subpockets of the factor Xa enzyme. Interactions with the subpockets were probed by systematic substitution of the 2-carboxyindole scaffold, in combination with privileged P1 and P4 substituents. Combining the most favorable substituents at the indole nucleus led to the discovery of a remarkably potent factor Xa inhibitor displaying a K(i) value of 0.07 nM. X-ray crystallography of inhibitors bound to factor Xa revealed substituent-dependent switching of the inhibitor binding mode and provided a rationale for the SAR obtained. These results underscore the key role played by the P1 ligand not only in determining the binding affinity of the inhibitor by direct interaction but also in modifying the binding mode of the whole scaffold, resulting in a nonlinear SAR.

PubMed: 15999990
DOI: 10.1021/JM0490540

Experimental method

X-RAY DIFFRACTION (2.2 Å)