2bqw

File:2bqw.gif

spinqualitylabelsall models 2bqw, resolution 2.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45

OverviewOverview

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.

DiseaseDisease

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

About this StructureAbout this Structure

2BQW is a Single protein structure of sequence from Homo sapiens with CA and IIE as ligands. Active as Coagulation factor Xa, with EC number 3.4.21.6 Known structural/functional Site: . Full crystallographic information is available from OCA.

ReferenceReference

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., Nazare M, Will DW, Matter H, Schreuder H, Ritter K, Urmann M, Essrich M, Bauer A, Wagner M, Czech J, Lorenz M, Laux V, Wehner V, J Med Chem. 2005 Jul 14;48(14):4511-25. PMID:15999990

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