2v22: Difference between revisions

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Revision as of 19:42, 20 March 2008

File:2v22.jpg

, resolution 2.60Å

Sites:

and

Ligands:

Activity:

Non-specific serine/threonine protein kinase, with EC number 2.7.11.1

Coordinates:

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REPLACE: A STRATEGY FOR ITERATIVE DESIGN OF CYCLIN BINDING GROOVE INHIBITORS

OverviewOverview

We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.

About this StructureAbout this Structure

2V22 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors., Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM, Chembiochem. 2006 Dec;7(12):1909-15. PMID:17051658

Page seeded by OCA on Thu Mar 20 18:42:28 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:2v22.jpg|left|200px]]<br /><applet load="2v22" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:2v22.jpg|left|200px]]
-caption="2v22, resolution 2.60&Aring;" />
-'''REPLACE: A STRATEGY FOR ITERATIVE DESIGN OF CYCLIN BINDING GROOVE INHIBITORS'''<br />
+ {{Structure
+|PDB= 2v22 |SIZE=350|CAPTION= <scene name='initialview01'>2v22</scene>, resolution 2.60&Aring;
+|SITE= <scene name='pdbsite=AC1:C35+Binding+Site+For+Residue+B+1433'>AC1</scene> and <scene name='pdbsite=AC2:C35+Binding+Site+For+Residue+D+1433'>AC2</scene>
+|LIGAND= <scene name='pdbligand=C35:N~2~-{[1-(4-CHLOROPHENYL)-5-METHYL-1H-1,2,4-TRIAZOL-3-YL]CARBONYL}-N~5~-(DIAMINOMETHYLIDENE)-L-ORNITHYL-L-LEUCYL-L-ISOLEUCYL-4-FLUORO-L-PHENYLALANINAMIDE'>C35</scene>
+|ACTIVITY= [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1]
+|GENE=
+}}
+'''REPLACE: A STRATEGY FOR ITERATIVE DESIGN OF CYCLIN BINDING GROOVE INHIBITORS'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-V22 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=C35:'>C35</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Known structural/functional Sites: <scene name='pdbsite=AC1:C35+Binding+Site+For+Residue+B+1433'>AC1</scene> and <scene name='pdbsite=AC2:C35+Binding+Site+For+Residue+D+1433'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V22 OCA].
+V22 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=2V22 OCA].
 ==Reference==
-REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors., Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM, Chembiochem. 2006 Dec;7(12):1909-15. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17051658 17051658]
+REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors., Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM, Chembiochem. 2006 Dec;7(12):1909-15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17051658 17051658]
 [[Category: Homo sapiens]]
 [[Category: Non-specific serine/threonine protein kinase]]
@@ Line 40: / Line 49: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:52:39 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:42:28 2008''