3kab: Difference between revisions

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{{STRUCTURE_3kab|  PDB=3kab  |  SCENE=  }}
==Structure-guided design of alpha-amino acid-derived Pin1 inhibitors==
===Structure-guided design of alpha-amino acid-derived Pin1 inhibitors===
<StructureSection load='3kab' size='340' side='right' caption='[[3kab]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
{{ABSTRACT_PUBMED_19969456}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3kab]] 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=3KAB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KAB FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=12P:DODECAETHYLENE+GLYCOL'>12P</scene>, <scene name='pdbligand=4BL:6-METHYL-1H-INDOLE-2-CARBOXYLIC+ACID'>4BL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3kac|3kac]], [[3kad|3kad]], [[3kaf|3kaf]], [[3kag|3kag]], [[3kah|3kah]], [[3kai|3kai]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>
<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=3kab FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kab OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3kab RCSB], [http://www.ebi.ac.uk/pdbsum/3kab 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/ka/3kab_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 ==
The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) &lt;100nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10-50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.


==Function==
Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.,Potter AJ, Ray S, Gueritz L, Nunns CL, Bryant CJ, Scrace SF, Matassova N, Baker L, Dokurno P, Robinson DA, Surgenor AE, Davis B, Murray JB, Richardson CM, Moore JD Bioorg Med Chem Lett. 2010 Jan 15;20(2):586-90. Epub 2009 Nov 22. PMID:19969456<ref>PMID:19969456</ref>
[[http://www.uniprot.org/uniprot/PIN1_HUMAN PIN1_HUMAN]] Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.<ref>PMID:15664191</ref> <ref>PMID:16644721</ref> <ref>PMID:21497122</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3kab]] 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=3KAB OCA].
</div>
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:019969456</ref><references group="xtra"/><references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Peptidylprolyl isomerase]]
[[Category: Peptidylprolyl isomerase]]
[[Category: Baker, L M.]]
[[Category: Baker, L M]]
[[Category: Dokurno, P.]]
[[Category: Dokurno, P]]
[[Category: Moore, J D.]]
[[Category: Moore, J D]]
[[Category: Murray, J B.]]
[[Category: Murray, J B]]
[[Category: Potter, A J.]]
[[Category: Potter, A J]]
[[Category: Robinson, D A.]]
[[Category: Robinson, D A]]
[[Category: Surgenor, A E.]]
[[Category: Surgenor, A E]]
[[Category: Cell cycle]]
[[Category: Cell cycle]]
[[Category: Isomerase]]
[[Category: Isomerase]]

Revision as of 18:19, 18 December 2014

Structure-guided design of alpha-amino acid-derived Pin1 inhibitorsStructure-guided design of alpha-amino acid-derived Pin1 inhibitors

Structural highlights

3kab 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:, ,
Gene:PIN1 (Homo sapiens)
Activity:Peptidylprolyl isomerase, with EC number 5.2.1.8
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

The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) <100nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10-50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.

Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.,Potter AJ, Ray S, Gueritz L, Nunns CL, Bryant CJ, Scrace SF, Matassova N, Baker L, Dokurno P, Robinson DA, Surgenor AE, Davis B, Murray JB, Richardson CM, Moore JD Bioorg Med Chem Lett. 2010 Jan 15;20(2):586-90. Epub 2009 Nov 22. PMID:19969456[1]

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

References

  1. ↑ Potter AJ, Ray S, Gueritz L, Nunns CL, Bryant CJ, Scrace SF, Matassova N, Baker L, Dokurno P, Robinson DA, Surgenor AE, Davis B, Murray JB, Richardson CM, Moore JD. Structure-guided design of alpha-amino acid-derived Pin1 inhibitors. Bioorg Med Chem Lett. 2010 Jan 15;20(2):586-90. Epub 2009 Nov 22. PMID:19969456 doi:10.1016/j.bmcl.2009.11.090

3kab, resolution 2.19Å

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