1f0r
From Proteopedia
(New page: 200px<br /> <applet load="1f0r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1f0r, resolution 2.10Å" /> '''CRYSTAL STRUCTURE O...) |
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| - | [[Image:1f0r.gif|left|200px]]<br /> | + | [[Image:1f0r.gif|left|200px]]<br /><applet load="1f0r" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1f0r" size=" | + | |
caption="1f0r, resolution 2.10Å" /> | caption="1f0r, resolution 2.10Å" /> | ||
'''CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR208815'''<br /> | '''CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR208815'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Involved in the coagulation cascade, factor Xa (FXa) is a serine protease | + | Involved in the coagulation cascade, factor Xa (FXa) is a serine protease which has received great interest as a potential target for the development of new antithrombotics. Although there is a great wealth of structural data on thrombin complexes, few structures of ligand/FXa complexes have been reported, presumably because of the difficulty in growing crystals. Reproducible crystallization conditions for human des-Gla1-45 coagulation FXa have been found. This has led to an improvement in the diffraction quality of the crystals (about 2.1 A) when compared to the previously reported forms (2.3-2.8 A) thus providing a suitable platform for a structure-based drug design approach. A series of crystal structures of noncovalent inhibitors complexed with FXa have been determined, three of which are presented herein. These include compounds containing the benzamidine moiety and surrogates of the basic group. The benzamidine-containing compound binds in a canonical fashion typical of synthetic serine protease inhibitors. On the contrary, molecules that contain surrogates of the benzamidine group do not make direct hydrogen-bonding interactions with the carboxylate of Asp189 at the bottom of the S1 pocket. The structural data provide a likely explanation for the specificity of these inhibitors and a great aid in the design of bioavailable potent FXa inhibitors. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1F0R is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA and 815 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] Full crystallographic information is available from [http:// | + | 1F0R is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=815:'>815</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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1F0R OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Becker, M | + | [[Category: Becker, M R.]] |
| - | [[Category: Choi-Sledeski, Y | + | [[Category: Choi-Sledeski, Y M.]] |
| - | [[Category: Ewing, W | + | [[Category: Ewing, W R.]] |
| - | [[Category: Guilloteau, J | + | [[Category: Guilloteau, J P.]] |
| - | [[Category: Klein, S | + | [[Category: Klein, S I.]] |
[[Category: Maignan, S.]] | [[Category: Maignan, S.]] | ||
[[Category: Mikol, V.]] | [[Category: Mikol, V.]] | ||
| - | [[Category: Pauls, H | + | [[Category: Pauls, H W.]] |
[[Category: Pouzieux, S.]] | [[Category: Pouzieux, S.]] | ||
| - | [[Category: Spada, A | + | [[Category: Spada, A P.]] |
[[Category: 815]] | [[Category: 815]] | ||
[[Category: CA]] | [[Category: CA]] | ||
[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:33:34 2008'' |
Revision as of 10:33, 21 February 2008
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CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR208815
Contents |
Overview
Involved in the coagulation cascade, factor Xa (FXa) is a serine protease which has received great interest as a potential target for the development of new antithrombotics. Although there is a great wealth of structural data on thrombin complexes, few structures of ligand/FXa complexes have been reported, presumably because of the difficulty in growing crystals. Reproducible crystallization conditions for human des-Gla1-45 coagulation FXa have been found. This has led to an improvement in the diffraction quality of the crystals (about 2.1 A) when compared to the previously reported forms (2.3-2.8 A) thus providing a suitable platform for a structure-based drug design approach. A series of crystal structures of noncovalent inhibitors complexed with FXa have been determined, three of which are presented herein. These include compounds containing the benzamidine moiety and surrogates of the basic group. The benzamidine-containing compound binds in a canonical fashion typical of synthetic serine protease inhibitors. On the contrary, molecules that contain surrogates of the benzamidine group do not make direct hydrogen-bonding interactions with the carboxylate of Asp189 at the bottom of the S1 pocket. The structural data provide a likely explanation for the specificity of these inhibitors and a great aid in the design of bioavailable potent FXa inhibitors.
Disease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this Structure
1F0R is a Protein complex structure of sequences from Homo sapiens with and as ligands. Active as Coagulation factor Xa, with EC number 3.4.21.6 Full crystallographic information is available from OCA.
Reference
Crystal structures of human factor Xa complexed with potent inhibitors., Maignan S, Guilloteau JP, Pouzieux S, Choi-Sledeski YM, Becker MR, Klein SI, Ewing WR, Pauls HW, Spada AP, Mikol V, J Med Chem. 2000 Aug 24;43(17):3226-32. PMID:10966741
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