4tyo

From Proteopedia

(Difference between revisions)

Revision as of 15:47, 5 August 2016

PPIase in complex with a non-phosphate small molecule inhibitor.

Structural highlights

4tyo is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	3i6c, 3jyj, 3ikg, 3ik8, 3ikd
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

The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.

Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocket.,Guo C, Hou X, Dong L, Marakovits J, Greasley S, Dagostino E, Ferre R, Catherine Johnson M, Humphries PS, Li H, Paderes GD, Piraino J, Kraynov E, Murray BW Bioorg Med Chem Lett. 2014 Jul 22. pii: S0960-894X(14)00768-9. doi:, 10.1016/j.bmcl.2014.07.044. PMID:25091930^[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
↑ Guo C, Hou X, Dong L, Marakovits J, Greasley S, Dagostino E, Ferre R, Catherine Johnson M, Humphries PS, Li H, Paderes GD, Piraino J, Kraynov E, Murray BW. Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocket. Bioorg Med Chem Lett. 2014 Jul 22. pii: S0960-894X(14)00768-9. doi:, 10.1016/j.bmcl.2014.07.044. PMID:25091930 doi:http://dx.doi.org/10.1016/j.bmcl.2014.07.044

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4tyo"

@@ Line 1: / Line 1: @@
 ==PPIase in complex with a non-phosphate small molecule inhibitor.==
 <StructureSection load='4tyo' size='340' side='right' caption='[[4tyo]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3i6c|3i6c]], [[3jyj|3jyj]], [[3ikg|3ikg]], [[3ik8|3ik8]], [[3ikd|3ikd]]</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=4tyo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tyo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tyo RCSB], [http://www.ebi.ac.uk/pdbsum/4tyo 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=4tyo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tyo OCA], [http://pdbe.org/4tyo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tyo RCSB], [http://www.ebi.ac.uk/pdbsum/4tyo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tyo 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 4tyo" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peptidyl-prolyl cis-trans isomerase|Peptidyl-prolyl cis-trans isomerase]]
 == References ==
 <references/>

4tyo

From Proteopedia

Revision as of 15:47, 5 August 2016

PPIase in complex with a non-phosphate small molecule inhibitor.

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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