9ja8

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Current revision (06:28, 29 January 2025) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 9ja8 is ON HOLD until Paper Publication
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==Crystal structure of human phosphodiesterase 10A in complex with N-(2-amino-2-thioxoethyl)-2-(3-(3-(dimethylcarbamoyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)azetidin-1-yl)quinoline-4-carboxamide==
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<StructureSection load='9ja8' size='340' side='right'caption='[[9ja8]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[9ja8]] 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=9JA8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9JA8 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L31:~{N}-(2-azanyl-2-sulfanylidene-ethyl)-2-[3-[3-(dimethylcarbamoyl)-6-fluoranyl-imidazo[1,2-a]pyridin-2-yl]azetidin-1-yl]quinoline-4-carboxamide'>A1L31</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9ja8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ja8 OCA], [https://pdbe.org/9ja8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ja8 RCSB], [https://www.ebi.ac.uk/pdbsum/9ja8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ja8 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-beta (TGF-beta)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H(2)S)-donor hybrid PDE10A inhibitor called COS-2080 with a well-defined mechanism of H(2)S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, COS-2080 demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called COS-2080-DPI has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of COS-2080 on TGF-beta1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, COS-2080 effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-beta signaling and activating the cAMP/PKA/CREB/p53 axis.
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Authors: Zhang, F.C., Huang, Y.Y., Luo, H.B., Guo, L.
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Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-beta Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis.,Wang Q, Liu X, Yuan H, Zhang F, Wu J, Yang D, Qian J, Huang YY, Chai G, Luo HB, Guo L ACS Pharmacol Transl Sci. 2024 Dec 28;8(1):256-269. doi: , 10.1021/acsptsci.4c00671. eCollection 2025 Jan 10. PMID:39816787<ref>PMID:39816787</ref>
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Description: Crystal structure of human phosphodiesterase 10A in complex with N-(2-amino-2-thioxoethyl)-2-(3-(3-(dimethylcarbamoyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)azetidin-1-yl)quinoline-4-carboxamide
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Huang, Y.Y]]
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<div class="pdbe-citations 9ja8" style="background-color:#fffaf0;"></div>
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[[Category: Guo, L]]
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== References ==
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[[Category: Luo, H.B]]
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<references/>
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[[Category: Zhang, F.C]]
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Guo L]]
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[[Category: Huang YY]]
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[[Category: Luo HB]]
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[[Category: Zhang FC]]

Current revision

Crystal structure of human phosphodiesterase 10A in complex with N-(2-amino-2-thioxoethyl)-2-(3-(3-(dimethylcarbamoyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)azetidin-1-yl)quinoline-4-carboxamide

PDB ID 9ja8

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