View source for 9inr


==Crystal structure of PIN1 in complex with inhibitor C3==
<StructureSection load='9inr' size='340' side='right'caption='[[9inr]], [[Resolution|resolution]] 1.93&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9inr]] 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=9INR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9INR 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]] 1.93&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1D9K:~{N}-[(2~{S})-3-[1-[4-(4-cyanophenyl)phenyl]-1,2,3-triazol-4-yl]-1-[(3-oxidanylcyclobutyl)amino]-1-oxidanylidene-propan-2-yl]-1-phenyl-cyclopropane-1-carboxamide'>A1D9K</scene>, <scene name='pdbligand=PE3:3,6,9,12,15,18,21,24,27,30,33,36,39-TRIDECAOXAHENTETRACONTANE-1,41-DIOL'>PE3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=9inr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9inr OCA], [https://pdbe.org/9inr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9inr RCSB], [https://www.ebi.ac.uk/pdbsum/9inr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9inr 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 ==
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC(50) = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC(50) = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy.

Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs.,Liu C, Chen Z, Chen T, Song H, Shen J, Yuan X, Xia S, Liu Q, Chen Q, Tian Q, Meng X, Han Z, Dong X, Yang Y, Cai L, Cheng X, Jia Y, Liu G, Li J, Ge J, Dou D J Med Chem. 2024 Sep 12;67(17):15780-15795. doi: 10.1021/acs.jmedchem.4c01412. , Epub 2024 Sep 4. PMID:39229909<ref>PMID:39229909</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9inr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Zhang LY]]