2xpa

From Proteopedia

(Difference between revisions)

Revision as of 01:02, 25 December 2014

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

Structural highlights

2xpa 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:	1f8a, 1i8g, 1pin, 2xpb, 2xp3, 2xp5, 1nmw, 1zcn, 2xp4, 2f21, 2xp6, 2xp8, 1nmv, 2xp9, 2xp7, 1i8h, 1i6c
Activity:	Peptidylprolyl isomerase, with EC number 5.2.1.8
Resources:	FirstGlance, OCA, RCSB, PDBsum

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

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2xpa"

@@ Line 8: / Line 8: @@
 <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=2xpa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xpa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xpa RCSB], [http://www.ebi.ac.uk/pdbsum/2xpa PDBsum]</span></td></tr>
 </table>
+== Function ==
+[[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 24: @@
 [[Category: Homo sapiens]]
 [[Category: Peptidylprolyl isomerase]]
-[[Category: Baker, L.]]
+[[Category: Baker, L]]
-[[Category: Bryant, C J.]]
+[[Category: Bryant, C J]]
-[[Category: Davis, B E.]]
+[[Category: Davis, B E]]
-[[Category: Dokurno, P.]]
+[[Category: Dokurno, P]]
-[[Category: Fromont, C.]]
+[[Category: Fromont, C]]
-[[Category: Matossova, N.]]
+[[Category: Matossova, N]]
-[[Category: Moore, J D.]]
+[[Category: Moore, J D]]
-[[Category: Murray, J B.]]
+[[Category: Murray, J B]]
-[[Category: Northfield, C J.]]
+[[Category: Northfield, C J]]
-[[Category: Nunns, C.]]
+[[Category: Nunns, C]]
-[[Category: Oldfield, V.]]
+[[Category: Oldfield, V]]
-[[Category: Potter, A.]]
+[[Category: Potter, A]]
-[[Category: Ray, S.]]
+[[Category: Ray, S]]
-[[Category: Richardson, C M.]]
+[[Category: Richardson, C M]]
-[[Category: Robinson, D.]]
+[[Category: Robinson, D]]
-[[Category: Scrace, S F.]]
+[[Category: Scrace, S F]]
-[[Category: Surgenor, A E.]]
+[[Category: Surgenor, A E]]
 [[Category: Cell cycle]]
 [[Category: Isomerase]]

2xpa

From Proteopedia

Revision as of 01:02, 25 December 2014

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

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox