1c2k: Difference between revisions

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Revision as of 11:19, 20 March 2008

File:1c2k.gif

, resolution 1.65Å

Ligands:

, , and

Activity:

Trypsin, with EC number 3.4.21.4

Coordinates:

save as pdb, mmCIF, xml

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

1C2K 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 Thu Mar 20 10:19:03 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:1c2k.gif|left|200px]]<br /><applet load="1c2k" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:1c2k.gif|left|200px]]
-caption="1c2k, resolution 1.65&Aring;" />
-'''RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES'''<br />
+ {{Structure
+|PDB= 1c2k |SIZE=350|CAPTION= <scene name='initialview01'>1c2k</scene>, resolution 1.65&Aring;
+|SITE=
+|LIGAND= <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> and <scene name='pdbligand=ABI:5-AMIDINO-BENZIMIDAZOLE'>ABI</scene>
+|ACTIVITY= [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]
+|GENE=
+}}
+'''RECRUITING ZINC TO MEDIATE POTENT, SPECIFIC INHIBITION OF SERINE PROTEASES'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-C2K is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=ABI:'>ABI</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C2K OCA].
+C2K is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C2K 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=9468142 9468142]
+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:[http://www.ncbi.nlm.nih.gov/pubmed/9468142 9468142]
 [[Category: Bos taurus]]
 [[Category: Single protein]]
@@ Line 23: / Line 32: @@
 [[Category: serine protease/inhibitor]]
 [[Category: zn(ii) affinity stucture-based drug design]]
-[[Category: zn(ii)-mediated serine protease inhibitors]]
+[[Category: zn(ii)-mediated serine protease inhibitor]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:01:43 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:19:03 2008''