2ra0: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 4: | Line 4: | ||
|PDB= 2ra0 |SIZE=350|CAPTION= <scene name='initialview01'>2ra0</scene>, resolution 2.30Å | |PDB= 2ra0 |SIZE=350|CAPTION= <scene name='initialview01'>2ra0</scene>, resolution 2.30Å | ||
|SITE= <scene name='pdbsite=AC1:Jnj+Binding+Site+For+Residue+A+1'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Jnj+Binding+Site+For+Residue+A+1'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand=JNJ:'>JNJ</scene> | |LIGAND= <scene name='pdbligand=JNJ:1-(3-AMINO-1,2-BENZISOXAZOL-5-YL)-6-(4-{2-[(DIMETHYLAMINO)METHYL]-1H-IMIDAZOL-1-YL}-2-FLUOROPHENYL)-7-FLUORO-1H-INDAZOLE-3-CARBOXAMIDE'>JNJ</scene> | ||
|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] | |ACTIVITY= <span class='plainlinks'>[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] </span> | ||
|GENE= F10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= F10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ra0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ra0 OCA], [http://www.ebi.ac.uk/pdbsum/2ra0 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ra0 RCSB]</span> | |||
}} | }} | ||
| Line 14: | Line 17: | ||
==Overview== | ==Overview== | ||
We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described. | We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described. | ||
==Disease== | |||
Known disease associated with this structure: Factor X deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=227600 227600]] | |||
==About this Structure== | ==About this Structure== | ||
| Line 24: | Line 30: | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Abad, M C.]] | [[Category: Abad, M C.]] | ||
[[Category: blood coagulation]] | [[Category: blood coagulation]] | ||
[[Category: calcium]] | [[Category: calcium]] | ||
| Line 37: | Line 42: | ||
[[Category: zymogen]] | [[Category: zymogen]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:58:01 2008'' | ||
