2brh: Difference between revisions

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Revision as of 17:05, 20 March 2008

File:2brh.gif

, resolution 2.10Å

Sites:

Ligands:

Activity:

Transferred entry: 2.7.11.1, with EC number 2.7.1.37

Coordinates:

save as pdb, mmCIF, xml

STRUCTURE-BASED DESIGN OF NOVEL CHK1 INHIBITORS: INSIGHTS INTO HYDROGEN BONDING AND PROTEIN-LIGAND AFFINITY

OverviewOverview

We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition.

About this StructureAbout this Structure

2BRH is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity., Foloppe N, Fisher LM, Howes R, Kierstan P, Potter A, Robertson AG, Surgenor AE, J Med Chem. 2005 Jun 30;48(13):4332-45. PMID:15974586

Page seeded by OCA on Thu Mar 20 16:05:43 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:2brh.gif|left|200px]]<br /><applet load="2brh" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:2brh.gif|left|200px]]
-caption="2brh, resolution 2.10&Aring;" />
-'''STRUCTURE-BASED DESIGN OF NOVEL CHK1 INHIBITORS: INSIGHTS INTO HYDROGEN BONDING AND PROTEIN-LIGAND AFFINITY'''<br />
+ {{Structure
+|PDB= 2brh |SIZE=350|CAPTION= <scene name='initialview01'>2brh</scene>, resolution 2.10&Aring;
+|SITE= <scene name='pdbsite=AC1:Dfw+Binding+Site+For+Chain+A'>AC1</scene>
+|LIGAND= <scene name='pdbligand=DFW:N-(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)GLYCINE'>DFW</scene>
+|ACTIVITY= [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37]
+|GENE=
+}}
+'''STRUCTURE-BASED DESIGN OF NOVEL CHK1 INHIBITORS: INSIGHTS INTO HYDROGEN BONDING AND PROTEIN-LIGAND AFFINITY'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-BRH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=DFW:'>DFW</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Known structural/functional Site: <scene name='pdbsite=AC1:Dfw+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BRH OCA].
+BRH is a [[Single protein]] structure of sequence 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=2BRH OCA].
 ==Reference==
-Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity., Foloppe N, Fisher LM, Howes R, Kierstan P, Potter A, Robertson AG, Surgenor AE, J Med Chem. 2005 Jun 30;48(13):4332-45. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=15974586 15974586]
+Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity., Foloppe N, Fisher LM, Howes R, Kierstan P, Potter A, Robertson AG, Surgenor AE, J Med Chem. 2005 Jun 30;48(13):4332-45. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15974586 15974586]
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
@@ Line 37: / Line 46: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:40:49 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:05:43 2008''