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| | ==Structure-Based Design of Novel PIN1 Inhibitors (I)== | | ==Structure-Based Design of Novel PIN1 Inhibitors (I)== |
| - | <StructureSection load='3ikg' size='340' side='right' caption='[[3ikg]], [[Resolution|resolution]] 1.86Å' scene=''> | + | <StructureSection load='3ikg' size='340' side='right'caption='[[3ikg]], [[Resolution|resolution]] 1.86Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ikg]] is a 2 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=3IKG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3IKG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ikg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IKG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IKG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J8Z:(2R)-2-[(1-BENZOTHIOPHEN-2-YLCARBONYL)AMINO]-3-(3-METHYLPHENYL)PROPYL+PHOSPHATE'>J8Z</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.86Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3i6c|3i6c]], [[3ik8|3ik8]], [[3ikd|3ikd]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J8Z:(2R)-2-[(1-BENZOTHIOPHEN-2-YLCARBONYL)AMINO]-3-(3-METHYLPHENYL)PROPYL+PHOSPHATE'>J8Z</scene></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 HUMAN])</td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ikg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ikg OCA], [https://pdbe.org/3ikg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ikg RCSB], [https://www.ebi.ac.uk/pdbsum/3ikg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ikg ProSAT]</span></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=3ikg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ikg OCA], [http://pdbe.org/3ikg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ikg RCSB], [http://www.ebi.ac.uk/pdbsum/3ikg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ikg ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [https://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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </div> | | </div> |
| | <div class="pdbe-citations 3ikg" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 3ikg" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Peptidyl-prolyl cis-trans isomerase 3D structures|Peptidyl-prolyl cis-trans isomerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Peptidylprolyl isomerase]] | + | [[Category: Large Structures]] |
| - | [[Category: Ferre, R A]] | + | [[Category: Ferre RA]] |
| - | [[Category: Greasley, S]] | + | [[Category: Greasley S]] |
| - | [[Category: Matthews, D]] | + | [[Category: Matthews D]] |
| - | [[Category: Parge, H]] | + | [[Category: Parge H]] |
| - | [[Category: Cell cycle]]
| + | |
| - | [[Category: Isomerase]]
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| - | [[Category: Nucleus]]
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| - | [[Category: Peptidyl-prolyl cis-trans isomerase]]
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| - | [[Category: Phosphoprotein]]
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| - | [[Category: Ppiase]]
| + | |
| - | [[Category: Rotamase]]
| + | |
| - | [[Category: Sbdd]]
| + | |
| - | [[Category: Small molecule]]
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| Structural highlights
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]
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
Pin1 is a member of the cis-trans peptidyl-prolyl isomerase family with potential anti-cancer therapeutic value. Here we report structure-based de novo design and optimization of novel Pin1 inhibitors. Without a viable lead from internal screenings, we designed a series of novel Pin1 inhibitors by interrogating and exploring a protein crystal structure of Pin1. The ligand efficiency of the initial concept molecule was optimized with integrated SBDD and parallel chemistry approaches, resulting in a more attractive lead series.
Structure-based design of novel human Pin1 inhibitors (I).,Guo C, Hou X, Dong L, Dagostino E, Greasley S, Ferre R, Marakovits J, Johnson MC, Matthews D, Mroczkowski B, Parge H, Vanarsdale T, Popoff I, Piraino J, Margosiak S, Thomson J, Los G, Murray BW Bioorg Med Chem Lett. 2009 Oct 1;19(19):5613-6. Epub 2009 Aug 13. PMID:19729306[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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, Dagostino E, Greasley S, Ferre R, Marakovits J, Johnson MC, Matthews D, Mroczkowski B, Parge H, Vanarsdale T, Popoff I, Piraino J, Margosiak S, Thomson J, Los G, Murray BW. Structure-based design of novel human Pin1 inhibitors (I). Bioorg Med Chem Lett. 2009 Oct 1;19(19):5613-6. Epub 2009 Aug 13. PMID:19729306 doi:10.1016/j.bmcl.2009.08.034
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