1xkb: Difference between revisions
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'''FACTOR XA COMPLEXED WITH A SYNTHETIC INHIBITOR FX-2212A,(2S)-(3'-AMIDINO-3-BIPHENYLYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID'''<br /> | '''FACTOR XA COMPLEXED WITH A SYNTHETIC INHIBITOR FX-2212A,(2S)-(3'-AMIDINO-3-BIPHENYLYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID'''<br /> | ||
==Overview== | ==Overview== | ||
Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged | Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged as an alternative (to thrombin) target for drug discovery for thromboembolic diseases. An inhibitor has been synthesized and the crystal structure of the complex between Des[1-44] factor Xa and the inhibitor has been determined by crystallographic methods in two different crystal forms to 2.3- and 2.4-A resolution. The racemic mixture of inhibitor FX-2212, (2RS)-(3'-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits factor Xa activity by 50% at 272 nM in vitro. The S-isomer of FX-2212 (FX-2212a) was found to bind to the active site of factor Xa in both crystal forms. The biphenylamidine of FX-2212a occupies the S1-pocket, and the pyridine ring makes hydrophobic interactions with the factor Xa aryl-binding site. Several water molecules meditate inhibitor binding to residues in the active site. In contrast to the earlier crystal structures of factor Xa, such as those of apo-Des[1-45] factor Xa and Des[1-44] factor Xa in complex with a naphthyl inhibitor DX-9065a, two epidermal growth factor-like domains of factor Xa are well ordered in both our crystal forms as well as the region between the two domains, which recently was found to be the binding site of the effector cell protease receptor-1. This structure provides a basis for designing next generation inhibitors of factor Xa. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
1XKB 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 4PP 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:// | 1XKB 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=4PP:'>4PP</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=1XKB OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Kamata, K.]] | [[Category: Kamata, K.]] | ||
[[Category: Kim, S | [[Category: Kim, S H.]] | ||
[[Category: 4PP]] | [[Category: 4PP]] | ||
[[Category: CA]] | [[Category: CA]] | ||
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[[Category: serine proteinase]] | [[Category: serine proteinase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:55:40 2008'' | ||
Revision as of 16:55, 21 February 2008
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FACTOR XA COMPLEXED WITH A SYNTHETIC INHIBITOR FX-2212A,(2S)-(3'-AMIDINO-3-BIPHENYLYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID
OverviewOverview
Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged as an alternative (to thrombin) target for drug discovery for thromboembolic diseases. An inhibitor has been synthesized and the crystal structure of the complex between Des[1-44] factor Xa and the inhibitor has been determined by crystallographic methods in two different crystal forms to 2.3- and 2.4-A resolution. The racemic mixture of inhibitor FX-2212, (2RS)-(3'-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits factor Xa activity by 50% at 272 nM in vitro. The S-isomer of FX-2212 (FX-2212a) was found to bind to the active site of factor Xa in both crystal forms. The biphenylamidine of FX-2212a occupies the S1-pocket, and the pyridine ring makes hydrophobic interactions with the factor Xa aryl-binding site. Several water molecules meditate inhibitor binding to residues in the active site. In contrast to the earlier crystal structures of factor Xa, such as those of apo-Des[1-45] factor Xa and Des[1-44] factor Xa in complex with a naphthyl inhibitor DX-9065a, two epidermal growth factor-like domains of factor Xa are well ordered in both our crystal forms as well as the region between the two domains, which recently was found to be the binding site of the effector cell protease receptor-1. This structure provides a basis for designing next generation inhibitors of factor Xa.
DiseaseDisease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this StructureAbout this Structure
1XKB 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.
ReferenceReference
Structural basis for chemical inhibition of human blood coagulation factor Xa., Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH, Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6630-5. PMID:9618463
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