1c1v
From Proteopedia
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|PDB= 1c1v |SIZE=350|CAPTION= <scene name='initialview01'>1c1v</scene>, resolution 1.98Å | |PDB= 1c1v |SIZE=350|CAPTION= <scene name='initialview01'>1c1v</scene>, resolution 1.98Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=BAB:BIS(5-AMIDINO-BENZIMIDAZOLYL)METHANE'>BAB</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=TYS:SULFONATED+TYROSINE'>TYS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1c2d|1C2D]], [[1c2f|1C2F]], [[1c2g|1C2G]], [[1c2h|1C2H]], [[1c2i|1C2I]], [[1c2l|1C2L]], [[1c2m|1C2M]], [[1c1n|1C1N]], [[1c1o|1C1O]], [[1c1p|1C1P]], [[1c1q|1C1Q]], [[1c1r|1C1R]], [[1c1s|1C1S]], [[1c1t|1C1T]], [[1c1u|1C1U]], [[1c2e|1C2E]], [[1c1w|1C1W]], [[1c2j|1C2J]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1c1v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c1v OCA], [http://www.ebi.ac.uk/pdbsum/1c1v PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1c1v RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion. | Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Dysprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hyperprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]], Hypoprothrombinemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176930 176930]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Katz, B A.]] | [[Category: Katz, B A.]] | ||
[[Category: Luong, C.]] | [[Category: Luong, C.]] | ||
| - | [[Category: BAB]] | ||
| - | [[Category: NA]] | ||
| - | [[Category: ZN]] | ||
[[Category: ph dependence]] | [[Category: ph dependence]] | ||
[[Category: serine protease/inhibitor]] | [[Category: serine protease/inhibitor]] | ||
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[[Category: zn(ii)-mediated serine protease inhibitor]] | [[Category: zn(ii)-mediated serine protease inhibitor]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:12:52 2008'' |
Revision as of 16:12, 30 March 2008
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| , resolution 1.98Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , | ||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Related: | 1C2D, 1C2F, 1C2G, 1C2H, 1C2I, 1C2L, 1C2M, 1C1N, 1C1O, 1C1P, 1C1Q, 1C1R, 1C1S, 1C1T, 1C1U, 1C2E, 1C1W, 1C2J
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES
Overview
Many serine proteases are targets for therapeutic intervention because they often play key roles in disease. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 10(3)-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.
About this Structure
1C1V is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Design of potent selective zinc-mediated serine protease inhibitors., Katz BA, Clark JM, Finer-Moore JS, Jenkins TE, Johnson CR, Ross MJ, Luong C, Moore WR, Stroud RM, Nature. 1998 Feb 5;391(6667):608-12. PMID:9468142
Page seeded by OCA on Sun Mar 30 19:12:52 2008
