1c2m: Difference between revisions

Revision as of 12:15, 2 May 2008

RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES

OverviewOverview

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 StructureAbout this Structure

1C2M is a Single protein structure of sequence from Bos taurus. Full crystallographic information is available from OCA.

ReferenceReference

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 Fri May 2 12:15:29 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:1c2m.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 1c2m |SIZE=350|CAPTION= <scene name='initialview01'>1c2m</scene>, resolution 1.40&Aring;
+The line below this paragraph, containing "STRUCTURE_1c2m", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Trypsin Trypsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.4 3.4.21.4] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1c2m|  PDB=1c2m  |  SCENE=  }}
-|RELATEDENTRY=[[1c2d|1C2D]], [[1c2f|1C2F]], [[1c2g|1C2G]], [[1c2h|1C2H]], [[1c2i|1C2I]], [[1c2l|1C2L]], [[1c2e|1C2E]], [[1c1n|1C1N]], [[1c1o|1C1O]], [[1c1p|1C1P]], [[1c1q|1C1Q]], [[1c1r|1C1R]], [[1c1s|1C1S]], [[1c1t|1C1T]], [[1c1u|1C1U]], [[1c1v|1C1V]], [[1c1w|1C1W]], [[1c2j|1C2J]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1c2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c2m OCA], [http://www.ebi.ac.uk/pdbsum/1c2m PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1c2m RCSB]</span>
-}}
 '''RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES'''
@@ Line 28: / Line 25: @@
 [[Category: Katz, B A.]]
 [[Category: Luong, C.]]
-[[Category: ph dependence]]
+[[Category: Ph dependence]]
-[[Category: serine protease]]
+[[Category: Serine protease]]
-[[Category: zn(ii) affinity stucture-based drug design]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 12:15:29 2008''
-[[Category: zn(ii)-mediated serine protease inhibitor]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:13:26 2008''