2bqw

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[[Image:2bqw.gif|left|200px]]<br /><applet load="2bqw" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2bqw.gif|left|200px]]
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caption="2bqw, resolution 2.95&Aring;" />
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'''CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45'''<br />
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{{Structure
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|PDB= 2bqw |SIZE=350|CAPTION= <scene name='initialview01'>2bqw</scene>, resolution 2.95&Aring;
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|SITE= <scene name='pdbsite=AC1:Iie+Binding+Site+For+Chain+B'>AC1</scene>
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|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene> and <scene name='pdbligand=IIE:1-{2-[(4-CHLOROPHENYL)AMINO]-2-OXOETHYL}-N-(1-ISOPROPYLPIPERIDIN-4-YL)-1H-INDOLE-2-CARBOXAMIDE'>IIE</scene>
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|ACTIVITY= [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]
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|GENE=
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}}
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'''CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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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 <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=IIE:'>IIE</scene> 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] Known structural/functional Site: <scene name='pdbsite=AC1:Iie+Binding+Site+For+Chain+B'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BQW OCA].
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2BQW is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BQW OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15999990 15999990]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/15999990 15999990]
[[Category: Coagulation factor Xa]]
[[Category: Coagulation factor Xa]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: zymogen]]
[[Category: zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:40:40 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:05:30 2008''

Revision as of 14:05, 20 March 2008

Image:2bqw.gif


PDB ID 2bqw

Drag the structure with the mouse to rotate
, resolution 2.95Å
Sites:
Ligands: and
Activity: Coagulation factor Xa, with EC number 3.4.21.6
Coordinates: save as pdb, mmCIF, xml



CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45


Contents

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 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.

Disease

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

About this Structure

2BQW is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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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