1ZOM

Crystal Structure of the Catalytic Domain of Coagulation Factor XI in complex with a peptidomimetic Inhibitor

Summary for 1ZOM

• Entry DOI: 10.2210/pdb1zom/pdb
• Descriptor: Coagulation factor XI, SULFATE ION, (S)-2-(3-((R)-1-(4-BROMOPHENYL)ETHYL)UREIDO)-N-((S)-1-((S)-5-GUANIDINO-1-OXO-1-(THIAZOL-2-YL)PENTAN-2-YLAMINO)-3-METHYL-1-OXOBUTAN-2-YL)-5-UREIDOPENTANAMIDE, ... (4 entities in total)
• Functional Keywords: fxia, inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P03951
• Total number of polymer chains: 1
• Total formula weight: 27574.13

Authors

Lin, J.,Deng, H.,Jin, L.,Pandey, P.,Rynkiewicz, M.,Bibbins, F.,Cantin, S.,Quinn, J.,Magee, S.,Gorga, J. (deposition date: 2005-05-13, release date: 2006-05-23, Last modification date: 2024-11-20)

Primary citation

Lin, J.,Deng, H.,Jin, L.,Pandey, P.,Quinn, J.,Cantin, S.,Rynkiewicz, M.J.,Gorga, J.C.,Bibbins, F.,Celatka, C.A.,Nagafuji, P.,Bannister, T.D.,Meyers, H.V.,Babine, R.E.,Hayward, N.J.,Weaver, D.,Benjamin, H.,Stassen, F.,Abdel-Meguid, S.S.,Strickler, J.E.
Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants.
J.Med.Chem., 49:7781-7791, 2006

PubMed Abstract: 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.

PubMed: 17181160
DOI: 10.1021/jm060978s

Experimental method

X-RAY DIFFRACTION (2.25 Å)