3fdn

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[[Image:3fdn.png|left|200px]]
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==Structure-based drug design of novel Aurora kinase A inhibitors: Structure basis for potency and specificity==
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<StructureSection load='3fdn' size='340' side='right' caption='[[3fdn]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3fdn]] 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=3FDN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FDN FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MMH:N-[3-(ACETYLAMINO)PHENYL]-5-{(2E)-2-[(4-METHOXYPHENYL)METHYLIDENE]HYDRAZINO}-3-METHYL-1H-PYRAZOLE-4-CARBOXAMIDE'>MMH</scene></td></tr>
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<tr id='activity'><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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3fdn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fdn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3fdn RCSB], [http://www.ebi.ac.uk/pdbsum/3fdn PDBsum]</span></td></tr>
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</table>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fd/3fdn_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Aurora kinases have emerged as attractive targets for the design of anticancer drugs. Through structure-based virtual screening, novel pyrazole hit 8a was identified as Aurora kinase A inhibitor (IC(50) = 15.1 microM). X-ray cocrystal structure of 8a in complex with Aurora A protein revealed the C-4 position ethyl carboxylate side chain as a possible modification site for improving the potency. On the basis of this insight, bioisosteric replacement of the ester with amide linkage and changing the ethyl substituent to hydrophobic 3-acetamidophenyl ring led to the identification of 12w with a approximately 450-fold improved Aurora kinase A inhibition potency (IC(50) = 33 nM), compared to 8a. Compound 12w showed selective inhibition of Aurora A kinase over Aurora B/C, which might be due to the presence of a unique H-bond interaction between the 3-acetamido group and the Aurora A nonconserved Thr217 residue, which in Aurora B/C is Glu and found to sterically clash with the 3-acetamido group in modeling studies.
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{{STRUCTURE_3fdn| PDB=3fdn | SCENE= }}
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Structure-based drug design of novel Aurora kinase A inhibitors: structural basis for potency and specificity.,Coumar MS, Leou JS, Shukla P, Wu JS, Dixit AK, Lin WH, Chang CY, Lien TW, Tan UK, Chen CH, Hsu JT, Chao YS, Wu SY, Hsieh HP J Med Chem. 2009 Feb 26;52(4):1050-62. PMID:19140666<ref>PMID:19140666</ref>
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===Structure-based drug design of novel Aurora kinase A inhibitors: Structure basis for potency and specificity===
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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{{ABSTRACT_PUBMED_19140666}}
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==See Also==
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*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
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==About this Structure==
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== References ==
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[[3fdn]] 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=3FDN OCA].
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<references/>
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__TOC__
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==Reference==
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</StructureSection>
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<ref group="xtra">PMID:019140666</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Coumar, M S.]]
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[[Category: Coumar, M S]]
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[[Category: Hsieh, H P.]]
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[[Category: Hsieh, H P]]
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[[Category: Leou, J S.]]
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[[Category: Leou, J S]]
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[[Category: Shukla, P.]]
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[[Category: Shukla, P]]
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[[Category: Wu, J S.]]
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[[Category: Wu, J S]]
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[[Category: Wu, S Y.]]
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[[Category: Wu, S Y]]
[[Category: Atp-binding]]
[[Category: Atp-binding]]
[[Category: Aurora kinase inhibitor]]
[[Category: Aurora kinase inhibitor]]
[[Category: Cell cycle]]
[[Category: Cell cycle]]
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[[Category: H-bonding.]]
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[[Category: H-bonding]]
[[Category: Kinase]]
[[Category: Kinase]]
[[Category: Nucleotide-binding]]
[[Category: Nucleotide-binding]]

Revision as of 08:51, 26 November 2014

Structure-based drug design of novel Aurora kinase A inhibitors: Structure basis for potency and specificity

3fdn, resolution 1.90Å

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