7efj: Difference between revisions

Latest revision as of 09:24, 9 October 2024

Crystal Structure Analysis of human PIN1

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.992Å
Ligands:	J2C, PE8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

The unique proline isomerase peptidyl-prolyl isomerase NIMA-interacting-1 (Pin1) is reported to activate numerous cancer-driving pathways simultaneously, and aberrant Pin1 activation is present in many human cancers. Here, we identified a novel hit compound, ZL-Pin01, that covalently modified Pin1 at Cys113 with an half-maximal inhibitory concentration (IC50) of 1.33 +/- 0.07 muM through screening an in-house library. Crystallographic study drove the process of structure-guided optimization and led to the potent inhibitor ZL-Pin13 with an IC50 of 0.067 +/- 0.03 muM. We obtained four co-crystal structures of Pin1 complexed with inhibitors that elucidated the detailed binding mode of the derivatives with Pin1. Interestingly, the co-crystal of Pin1 with ZL-Pin13 obtained by co-crystallization revealed the conformational change of Gln129 induced by the inhibitor. Furthermore, ZL-Pin13 effectively inhibited the proliferation and downregulated the Pin1 substrates in MDA-MB-231 cells. Collectively, we developed a potent covalent inhibitor of Pin1, ZL-Pin13, which could be an effective probe for studying the functional roles of Pin1.

Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1).,Liu L, Zhu R, Li J, Pei Y, Wang S, Xu P, Wang M, Wen Y, Zhang H, Du D, Ding H, Jiang H, Chen K, Zhou B, Yu L, Luo C J Med Chem. 2022 Feb 10;65(3):2174-2190. doi: 10.1021/acs.jmedchem.1c01686. Epub , 2022 Jan 28. PMID:35089030^[1]

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

References

↑ Liu L, Zhu R, Li J, Pei Y, Wang S, Xu P, Wang M, Wen Y, Zhang H, Du D, Ding H, Jiang H, Chen K, Zhou B, Yu L, Luo C. Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1). J Med Chem. 2022 Feb 10;65(3):2174-2190. doi: 10.1021/acs.jmedchem.1c01686. Epub , 2022 Jan 28. PMID:35089030 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c01686

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Liu L, Zhu R, Li J, Pei Y, Wang S, Xu P, Wang M, Wen Y, Zhang H, Du D, Ding H, Jiang H, Chen K, Zhou B, Yu L, Luo C. Computational and Structure-Based Development of High Potent Cell-Active Covalent Inhibitor Targeting the Peptidyl-Prolyl Isomerase NIMA-Interacting-1 (Pin1). J Med Chem. 2022 Feb 10;65(3):2174-2190. doi: 10.1021/acs.jmedchem.1c01686. Epub , 2022 Jan 28. PMID:35089030 doi:https://dx.doi.org/10.1021/acs.jmedchem.1c01686

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='7efj' size='340' side='right'caption='[[7efj]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7efj]] is a 1 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=7EFJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EFJ FirstGlance]. <br>
+<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EFJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EFJ FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.992&#8491;</td></tr>
 <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=J2C:8-(2-chloroacetyl)-4-(furan-2-ylmethyl)-1-thia-4,8-diazaspiro[4.5]decan-3-one'>J2C</scene>, <scene name='pdbligand=PE8:3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL'>PE8</scene></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=7efj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7efj OCA], [https://pdbe.org/7efj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7efj RCSB], [https://www.ebi.ac.uk/pdbsum/7efj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7efj ProSAT]</span></td></tr>
 </table>
-== Function ==
-[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
 [[Category: Large Structures]]
 [[Category: Li J]]
 [[Category: Liu L]]

7efj: Difference between revisions

Latest revision as of 09:24, 9 October 2024

Crystal Structure Analysis of human PIN1

Structural highlights

Publication Abstract from PubMed

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References

Contents

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