2xp8: Difference between revisions

Revision as of 08:47, 5 August 2016

DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTIONDISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION

Structural highlights

2xp8 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1f8a, 1i8g, 1pin, 2xpb, 2xp3, 2xp5, 1nmw, 1zcn, 2xp4, 2f21, 2xp6, 1nmv, 2xp9, 2xp7, 1i8h, 2xpa, 1i6c
Activity:	Peptidylprolyl isomerase, with EC number 5.2.1.8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Pin1 is an emerging oncology target strongly implicated in Ras and ErbB2-mediated tumourigenesis. Pin1 isomerizes bonds linking phospho-serine/threonine moieties to proline enabling it to play a key role in proline-directed kinase signalling. Here we report a novel series of Pin1 inhibitors based on a phenyl imidazole acid core that contains sub-muM inhibitors. Compounds have been identified that block prostate cancer cell growth under conditions where Pin1 is essential.

Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution.,Potter A, Oldfield V, Nunns C, Fromont C, Ray S, Northfield CJ, Bryant CJ, Scrace SF, Robinson D, Matossova N, Baker L, Dokurno P, Surgenor AE, Davis B, Richardson CM, Murray JB, Moore JD Bioorg Med Chem Lett. 2010 Nov 15;20(22):6483-8. Epub 2010 Sep 17. PMID:20932746^[4]

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

References

↑ Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005 Jan 21;17(2):215-24. PMID:15664191 doi:10.1016/j.molcel.2004.11.055
↑ Yu L, Mohamed AJ, Vargas L, Berglof A, Finn G, Lu KP, Smith CI. Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. J Biol Chem. 2006 Jun 30;281(26):18201-7. Epub 2006 Apr 27. PMID:16644721 doi:10.1074/jbc.M603090200
↑ Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell. 2011 Apr 22;42(2):147-59. doi: 10.1016/j.molcel.2011.03.005. Epub 2011 , Apr 14. PMID:21497122 doi:10.1016/j.molcel.2011.03.005
↑ Potter A, Oldfield V, Nunns C, Fromont C, Ray S, Northfield CJ, Bryant CJ, Scrace SF, Robinson D, Matossova N, Baker L, Dokurno P, Surgenor AE, Davis B, Richardson CM, Murray JB, Moore JD. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6483-8. Epub 2010 Sep 17. PMID:20932746 doi:10.1016/j.bmcl.2010.09.063

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

OCA

[1] Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005 Jan 21;17(2):215-24. PMID:15664191 doi:10.1016/j.molcel.2004.11.055

[2] Yu L, Mohamed AJ, Vargas L, Berglof A, Finn G, Lu KP, Smith CI. Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. J Biol Chem. 2006 Jun 30;281(26):18201-7. Epub 2006 Apr 27. PMID:16644721 doi:10.1074/jbc.M603090200

[3] Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell. 2011 Apr 22;42(2):147-59. doi: 10.1016/j.molcel.2011.03.005. Epub 2011 , Apr 14. PMID:21497122 doi:10.1016/j.molcel.2011.03.005

[4] Potter A, Oldfield V, Nunns C, Fromont C, Ray S, Northfield CJ, Bryant CJ, Scrace SF, Robinson D, Matossova N, Baker L, Dokurno P, Surgenor AE, Davis B, Richardson CM, Murray JB, Moore JD. Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6483-8. Epub 2010 Sep 17. PMID:20932746 doi:10.1016/j.bmcl.2010.09.063

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
 ==DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION==
 <StructureSection load='2xp8' size='340' side='right' caption='[[2xp8]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2xp8]] 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=2XP8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XP8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2xp8]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XP8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XP8 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=4FY:4-(MORPHOLIN-4-YLCARBONYL)-2-PHENYL-1H-IMIDAZOLE-5-CARBOXYLIC+ACID'>4FY</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1f8a|1f8a]], [[1i8g|1i8g]], [[1pin|1pin]], [[2xpb|2xpb]], [[2xp3|2xp3]], [[2xp5|2xp5]], [[1nmw|1nmw]], [[1zcn|1zcn]], [[2xp4|2xp4]], [[2f21|2f21]], [[2xp6|2xp6]], [[1nmv|1nmv]], [[2xp9|2xp9]], [[2xp7|2xp7]], [[1i8h|1i8h]], [[2xpa|2xpa]], [[1i6c|1i6c]]</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=2xp8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xp8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xp8 RCSB], [http://www.ebi.ac.uk/pdbsum/2xp8 PDBsum]</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=2xp8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xp8 OCA], [http://pdbe.org/2xp8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xp8 RCSB], [http://www.ebi.ac.uk/pdbsum/2xp8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xp8 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2xp8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peptidyl-prolyl cis-trans isomerase|Peptidyl-prolyl cis-trans isomerase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Peptidylprolyl isomerase]]
 [[Category: Baker, L]]

2xp8: Difference between revisions

Revision as of 08:47, 5 August 2016

DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTIONDISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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

Navigation menu

2xp8: Difference between revisions

Revision as of 08:47, 5 August 2016

DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTIONDISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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

Navigation menu

Search