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| | {{STRUCTURE_1c1s| PDB=1c1s | SCENE= }} | | {{STRUCTURE_1c1s| PDB=1c1s | SCENE= }} |
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| - | '''RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES'''
| + | ===RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES=== |
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| - | ==Overview==
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| - | As regulators of ubiquitous biological processes, serine proteases can cause disease states when inappropriately expressed or regulated, and are thus rational targets for inhibition by drugs. Recently we described a new inhibition mechanism applicable for the development of potent, selective small molecule serine protease inhibitors that recruit physiological Zn2+ to mediate high affinity (sub-nanomolar) binding. To demonstrate some of the structural principles by which the selectivity of Zn2+-mediated serine protease inhibitors can be developed toward or against a particular target, here we determine and describe the structures of thrombin-BABIM-Zn2+, -keto-BABIM-Zn2+, and -hemi-BABIM-Zn2+ (where BABIM is bis(5-amidino-2-benzimidazolyl)methane, keto-BABIM is bis(5-amidino-2-benzimidazolyl)methane ketone, and hemi-BABIM is (5-amidino-2-benzimidazolyl)(2-benzimidazolyl)methane), and compare them with the corresponding trypsin-inhibitor-Zn2+ complexes. Inhibitor binding is mediated by a Zn ion tetrahedrally coordinated by two benzimidazole nitrogen atoms of the inhibitor, by N(epsilon2)His57, and by O(gamma)Ser195. The structures of Zn2+-free trypsin-BABIM and -hemi-BABIM were also determined at selected pH values for comparison with the corresponding Zn2+-mediated complexes. To assess some of the physiological parameters important for harnessing Zn2+ as a co-inhibitor, crystal structures at multiple pH and [Zn2+] values were determined for trypsin-keto-BABIM. The Kdvalue of Zn2+ for the binary trypsin-keto-BABIM complex was estimated to be <12 nM at pH 7.06 by crystallographic determination of the occupancy of bound Zn2+ in trypsin-keto-BABIM crystals soaked at this pH in synthetic mother liquor containing inhibitor and 100 nM Zn2+. In synthetic mother liquor saturated in Zn2+, trypsin-bound keto-BABIM is unhydrated at pH 9.00 and 9.93, and has an sp2 hybridized ketone carbon bridging the 5-amidinobenzimidazoles, whereas at pH 7.00 and 8.00 it undergoes hydration and a change in geometry upon addition of water to the bridging carbonyl group. To show how Zn2+ could be recruited as a co-inhibitor of other enzymes, a method was developed for locating in protein crystals Zn2+ binding sites where design of Zn2+-mediated ligands can be attempted. Thus, by soaking trypsin crystals in high concentrations of Zn2+ in the absence of a molecular inhibitor, the site where Zn2+ mediates binding of BABIM and analogs was identified, as well as another Zn2+ binding site.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10497030}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10497030 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10497030}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Ph dependence]] | | [[Category: Ph dependence]] |
| | [[Category: Serine protease/inhibitor]] | | [[Category: Serine protease/inhibitor]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 12:13:54 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 20:05:30 2008'' |
Revision as of 17:05, 30 June 2008
Template:STRUCTURE 1c1s
RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES
Template:ABSTRACT PUBMED 10497030
About this Structure
1C1S is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.
Reference
Recruiting Zn2+ to mediate potent, specific inhibition of serine proteases., Katz BA, Luong C, J Mol Biol. 1999 Sep 24;292(3):669-84. PMID:10497030
Page seeded by OCA on Mon Jun 30 20:05:30 2008
