1zom
From Proteopedia
(New page: 200px<br /> <applet load="1zom" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zom, resolution 2.25Å" /> '''Crystal Structure o...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1zom.gif|left|200px]]<br /> | + | [[Image:1zom.gif|left|200px]]<br /><applet load="1zom" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1zom" size=" | + | |
caption="1zom, resolution 2.25Å" /> | caption="1zom, resolution 2.25Å" /> | ||
'''Crystal Structure of the Catalytic Domain of Coagulation Factor XI in complex with a peptidomimetic Inhibitor'''<br /> | '''Crystal Structure of the Catalytic Domain of Coagulation Factor XI in complex with a peptidomimetic Inhibitor'''<br /> | ||
| Line 6: | Line 5: | ||
==Overview== | ==Overview== | ||
Human coagulation factor XIa (FXIa), a serine protease activated by, site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation, cascade. To investigate the potential of FXIa inhibitors as safe, anticoagulants, a series of potent, selective peptidomimetic inhibitors of, FXIa were designed and synthesized. Some of these inhibitors showed low, nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and, >100-fold thrombin selectivity. The X-ray structure of one of these, inhibitors, 36, demonstrates its unique binding interactions with FXIa., Compound 32 caused a doubling of the activated partial thromboplastin time, in human plasma at 2.4 microM and was efficacious in a rat model of venous, thrombosis. These data suggest that factor XIa plays a significant role in, venous thrombosis and may be a suitable target for the development of, antithrombotic therapy. | Human coagulation factor XIa (FXIa), a serine protease activated by, site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation, cascade. To investigate the potential of FXIa inhibitors as safe, anticoagulants, a series of potent, selective peptidomimetic inhibitors of, FXIa were designed and synthesized. Some of these inhibitors showed low, nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and, >100-fold thrombin selectivity. The X-ray structure of one of these, inhibitors, 36, demonstrates its unique binding interactions with FXIa., Compound 32 caused a doubling of the activated partial thromboplastin time, in human plasma at 2.4 microM and was efficacious in a rat model of venous, thrombosis. These data suggest that factor XIa plays a significant role in, venous thrombosis and may be a suitable target for the development of, antithrombotic therapy. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Factor XI deficiency, autosomal dominant OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=264900 264900]], Factor XI deficiency, autosomal recessive OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=264900 264900]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 1ZOM 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 SO4 and 339 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] Full crystallographic information is available from [http:// | + | 1ZOM 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=SO4:'>SO4</scene> and <scene name='pdbligand=339:'>339</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Coagulation_factor_XIa Coagulation factor XIa], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.27 3.4.21.27] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZOM OCA]. |
==Reference== | ==Reference== | ||
| Line 33: | Line 29: | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:29:48 2008'' |
Revision as of 13:29, 23 January 2008
|
Crystal Structure of the Catalytic Domain of Coagulation Factor XI in complex with a peptidomimetic Inhibitor
Overview
Human coagulation factor XIa (FXIa), a serine protease activated by, site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation, cascade. To investigate the potential of FXIa inhibitors as safe, anticoagulants, a series of potent, selective peptidomimetic inhibitors of, FXIa were designed and synthesized. Some of these inhibitors showed low, nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and, >100-fold thrombin selectivity. The X-ray structure of one of these, inhibitors, 36, demonstrates its unique binding interactions with FXIa., Compound 32 caused a doubling of the activated partial thromboplastin time, in human plasma at 2.4 microM and was efficacious in a rat model of venous, thrombosis. These data suggest that factor XIa plays a significant role in, venous thrombosis and may be a suitable target for the development of, antithrombotic therapy.
About this Structure
1ZOM is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Coagulation factor XIa, with EC number 3.4.21.27 Full crystallographic information is available from OCA.
Reference
Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants., Lin J, Deng H, Jin L, Pandey P, Quinn J, Cantin S, Rynkiewicz MJ, Gorga JC, Bibbins F, Celatka CA, Nagafuji P, Bannister TD, Meyers HV, Babine RE, Hayward NJ, Weaver D, Benjamin H, Stassen F, Abdel-Meguid SS, Strickler JE, J Med Chem. 2006 Dec 28;49(26):7781-91. PMID:17181160
Page seeded by OCA on Wed Jan 23 15:29:48 2008
Categories: Coagulation factor XIa | Homo sapiens | Single protein | Bibbins, F. | Cantin, S. | Deng, H. | Gorga, J. | Jin, L. | Lin, J. | Magee, S. | Pandey, P. | Quinn, J. | Rynkiewicz, M. | 339 | SO4 | Fxia | Inhibitor
