1mq5
From Proteopedia
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| - | [[Image:1mq5.jpg|left|200px]] | + | [[Image:1mq5.jpg|left|200px]] |
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| - | '''Crystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa''' | + | {{Structure |
| + | |PDB= 1mq5 |SIZE=350|CAPTION= <scene name='initialview01'>1mq5</scene>, resolution 2.10Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=XLC:3-CHLORO-N-[4-CHLORO-2-[[(4-CHLOROPHENYL)AMINO]CARBONYL]PHENYL]-4-[(4-METHYL-1-PIPERAZINYL)METHYL]-2-THIOPHENECARBOXAMIDE'>XLC</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</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] | ||
| + | |GENE= | ||
| + | }} | ||
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| + | '''Crystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa''' | ||
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==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1MQ5 is a [ | + | 1MQ5 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MQ5 OCA]. |
==Reference== | ==Reference== | ||
| - | Crystal structures of two potent nonamidine inhibitors bound to factor Xa., Adler M, Kochanny MJ, Ye B, Rumennik G, Light DR, Biancalana S, Whitlow M, Biochemistry. 2002 Dec 31;41(52):15514-23. PMID:[http:// | + | Crystal structures of two potent nonamidine inhibitors bound to factor Xa., Adler M, Kochanny MJ, Ye B, Rumennik G, Light DR, Biancalana S, Whitlow M, Biochemistry. 2002 Dec 31;41(52):15514-23. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12501180 12501180] |
[[Category: Coagulation factor Xa]] | [[Category: Coagulation factor Xa]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
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[[Category: protein inhibitor complex]] | [[Category: protein inhibitor complex]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 12:46:46 2008'' |
Revision as of 10:46, 20 March 2008
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| , resolution 2.10Å | |||||||
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| Ligands: | , and | ||||||
| Activity: | Coagulation factor Xa, with EC number 3.4.21.6 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa
Contents |
Overview
There has been intense interest in the development of factor Xa inhibitors for the treatment of thrombotic diseases. Our laboratory has developed a series of novel non-amidine inhibitors of factor Xa. This paper presents two crystal structures of compounds from this series bound to factor Xa. The first structure is derived from the complex formed between factor Xa and compound 1. Compound 1 was the first non-amidine factor Xa inhibitor from our lab that had measurable potency in an in vitro assay of anticoagulant activity. The second compound, 2, has a molar affinity for factor Xa (K(iapp)) of 7 pM and good bioavailability. The two inhibitors bind in an L-shaped conformation with a chloroaromatic ring buried deeply in the S1 pocket. The opposite end of these compounds contains a basic substituent that extends into the S4 binding site. A chlorinated phenyl ring bridges the substituents in the S1 and S4 pockets via amide linkers. The overall conformation is similar to the previously published structures for amidine-based inhibitors complexed with factor Xa. However, there are significant differences in the interactions between the inhibitor and the protein at the atomic level. Most notably, there is no group that forms a salt bridge with the carboxylic acid at the base of the S1 pocket (Asp189). Each inhibitor forms only one well-defined hydrogen bond to the protein. There are no direct charge-charge interactions. The results indicate that electrostatic interactions play a secondary role in the binding of these potent inhibitors.
Disease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this Structure
1MQ5 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structures of two potent nonamidine inhibitors bound to factor Xa., Adler M, Kochanny MJ, Ye B, Rumennik G, Light DR, Biancalana S, Whitlow M, Biochemistry. 2002 Dec 31;41(52):15514-23. PMID:12501180
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