2brh: Difference between revisions

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[[Image:2brh.png|left|200px]]
==STRUCTURE-BASED DESIGN OF NOVEL CHK1 INHIBITORS: INSIGHTS INTO HYDROGEN BONDING AND PROTEIN-LIGAND AFFINITY==
<StructureSection load='2brh' size='340' side='right' caption='[[2brh]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2brh]] is a 1 chain structure with 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]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2BRH FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DFW:N-(5,6-DIPHENYLFURO[2,3-D]PYRIMIDIN-4-YL)GLYCINE'>DFW</scene><br>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ia8|1ia8]], [[1nvq|1nvq]], [[1nvr|1nvr]], [[1nvs|1nvs]], [[2br1|2br1]], [[2brb|2brb]], [[2brg|2brg]], [[2brm|2brm]], [[2brn|2brn]], [[2bro|2bro]]</td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2brh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2brh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2brh RCSB], [http://www.ebi.ac.uk/pdbsum/2brh PDBsum]</span></td></tr>
<table>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/br/2brh_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


{{STRUCTURE_2brh|  PDB=2brh  |  SCENE=  }}
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<ref>PMID:15974586</ref>


===STRUCTURE-BASED DESIGN OF NOVEL CHK1 INHIBITORS: INSIGHTS INTO HYDROGEN BONDING AND PROTEIN-LIGAND AFFINITY===
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
{{ABSTRACT_PUBMED_15974586}}
 
==About this Structure==
[[2brh]] is a 1 chain structure with 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].


==See Also==
==See Also==
*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:015974586</ref><references group="xtra"/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]

Revision as of 07:01, 29 September 2014

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

Structural highlights

2brh is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:1ia8, 1nvq, 1nvr, 1nvs, 2br1, 2brb, 2brg, 2brm, 2brn, 2bro
Activity:Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:FirstGlance, OCA, RCSB, PDBsum

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Foloppe N, Fisher LM, Howes R, Kierstan P, Potter A, Robertson AG, Surgenor AE. Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity. J Med Chem. 2005 Jun 30;48(13):4332-45. PMID:15974586 doi:10.1021/jm049022c

2brh, resolution 2.10Å

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