2bqw: Difference between revisions
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==Overview== | ==Overview== | ||
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 . | 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. | ||
==About this Structure== | ==About this Structure== | ||
2BQW is a | 2BQW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA and IIE as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_Xa Coagulation factor Xa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.6 3.4.21.6] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BQW OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 14:22:17 2007'' | ||
Revision as of 15:16, 5 November 2007
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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.
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 Structure known Active Site: AC1. 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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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Coagulation factor Xa
- Homo sapiens
- Single protein
- Bauer, A.
- Czech, J.
- Essrich, M.
- Laux, V.
- Matter, H.
- Nazare, M.
- Ritter, K.
- Schreuder, H.
- Urmann, M.
- Wagner, M.
- Wehner, V.
- Will, D.W.
- CA
- IIE
- Blood coagulation
- Blood coagulation factor
- Calcium-binding
- Egf-like domain
- Gamma-carboxyglutamic acid
- Glycoprotein
- Hydrolase
- Hydroxylation
- Plasma
- Polymorphism
- Protein inhibitor complex
- Serine protease
- Serine proteinase
- Vitamin k
- Zymogen