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==X-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallization== | ==X-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallization== | ||
<StructureSection load='7e0a' size='340' side='right'caption='[[7e0a]]' scene=''> | <StructureSection load='7e0a' size='340' side='right'caption='[[7e0a]], [[Resolution|resolution]] 1.77Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E0A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E0A FirstGlance]. <br> | <table><tr><td colspan='2'>[[7e0a]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E0A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E0A FirstGlance]. <br> | ||
</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=7e0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e0a OCA], [https://pdbe.org/7e0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e0a RCSB], [https://www.ebi.ac.uk/pdbsum/7e0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e0a ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EWR:(2S)-2-ethoxy-3-[4-[2-[2-methyl-5-(4-methylsulfanylphenyl)pyrrol-1-yl]ethoxy]phenyl]propanoic+acid'>EWR</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPARG, NR1C3 ([https://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=7e0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e0a OCA], [https://pdbe.org/7e0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e0a RCSB], [https://www.ebi.ac.uk/pdbsum/7e0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e0a ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (alpha, gamma, and beta/delta) with distinct functions and PPAR dual/pan agonists are expected to be the next generation of drugs for metabolic diseases. Saroglitazar is the first clinically approved PPARalpha/gamma dual agonist for treatment of diabetic dyslipidemia and is currently in clinical trials to treat non-alcoholic fatty liver disease (NAFLD); however, the structural information of its interaction with PPARalpha/gamma remains unknown. We recently revealed the high-resolution co-crystal structure of saroglitazar and the PPARalpha-ligand binding domain (LBD) through X-ray crystallography, and in this study, we report the structure of saroglitazar and the PPARgamma-LBD. Saroglitazar was located at the center of "Y"-shaped PPARgamma-ligand-binding pocket (LBP), just as it was in the respective region of PPARalpha-LBP. Its carboxylic acid was attached to four amino acids (Ser289/His323/His449/Thr473), which contributes to the stabilization of Activating Function-2 helix 12, and its phenylpyrrole moiety was rotated 121.8 degrees in PPARgamma-LBD from that in PPARalpha-LBD to interact with Phe264. PPARdelta-LBD has the consensus four amino acids (Thr253/His287/His413/Tyr437) towards the carboxylic acids of its ligands, but it seems to lack sufficient space to accept saroglitazar because of the steric hindrance between the Trp228 or Arg248 residue of PPARdelta-LBD and its methylthiophenyl moiety. Accordingly, in a coactivator recruitment assay, saroglitazar activated PPARalpha-LBD and PPARgamma-LBD but not PPARdelta-LBD, whereas glycine substitution of either Trp228, Arg248, or both of PPARdelta-LBD conferred saroglitazar concentration-dependent activation. Our findings may be valuable in the molecular design of PPARalpha/gamma dual or PPARalpha/gamma/delta pan agonists. | |||
Structural Basis for Anti-non-alcoholic Fatty Liver Disease and Diabetic Dyslipidemia Drug Saroglitazar as a PPAR alpha/gamma Dual Agonist.,Honda A, Kamata S, Satta C, Machida Y, Uchii K, Terasawa K, Nemoto A, Oyama T, Ishii I Biol Pharm Bull. 2021;44(9):1210-1219. doi: 10.1248/bpb.b21-00232. PMID:34471049<ref>PMID:34471049</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7e0a" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Honda A]] | [[Category: Honda, A]] | ||
[[Category: Ishii I]] | [[Category: Ishii, I]] | ||
[[Category: Kamata S]] | [[Category: Kamata, S]] | ||
[[Category: Machida Y]] | [[Category: Machida, Y]] | ||
[[Category: Oyama T]] | [[Category: Oyama, T]] | ||
[[Category: Uchii K]] | [[Category: Uchii, K]] | ||
[[Category: Nuclear receptor]] | |||
[[Category: Ppar]] | |||
[[Category: Protein-ligand complex]] | |||
[[Category: Transcription]] | |||
Revision as of 09:59, 22 September 2021
X-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallizationX-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallization
Structural highlights
Publication Abstract from PubMedPeroxisome proliferator-activated receptors (PPARs) are nuclear receptor-type transcription factors that consist of three subtypes (alpha, gamma, and beta/delta) with distinct functions and PPAR dual/pan agonists are expected to be the next generation of drugs for metabolic diseases. Saroglitazar is the first clinically approved PPARalpha/gamma dual agonist for treatment of diabetic dyslipidemia and is currently in clinical trials to treat non-alcoholic fatty liver disease (NAFLD); however, the structural information of its interaction with PPARalpha/gamma remains unknown. We recently revealed the high-resolution co-crystal structure of saroglitazar and the PPARalpha-ligand binding domain (LBD) through X-ray crystallography, and in this study, we report the structure of saroglitazar and the PPARgamma-LBD. Saroglitazar was located at the center of "Y"-shaped PPARgamma-ligand-binding pocket (LBP), just as it was in the respective region of PPARalpha-LBP. Its carboxylic acid was attached to four amino acids (Ser289/His323/His449/Thr473), which contributes to the stabilization of Activating Function-2 helix 12, and its phenylpyrrole moiety was rotated 121.8 degrees in PPARgamma-LBD from that in PPARalpha-LBD to interact with Phe264. PPARdelta-LBD has the consensus four amino acids (Thr253/His287/His413/Tyr437) towards the carboxylic acids of its ligands, but it seems to lack sufficient space to accept saroglitazar because of the steric hindrance between the Trp228 or Arg248 residue of PPARdelta-LBD and its methylthiophenyl moiety. Accordingly, in a coactivator recruitment assay, saroglitazar activated PPARalpha-LBD and PPARgamma-LBD but not PPARdelta-LBD, whereas glycine substitution of either Trp228, Arg248, or both of PPARdelta-LBD conferred saroglitazar concentration-dependent activation. Our findings may be valuable in the molecular design of PPARalpha/gamma dual or PPARalpha/gamma/delta pan agonists. Structural Basis for Anti-non-alcoholic Fatty Liver Disease and Diabetic Dyslipidemia Drug Saroglitazar as a PPAR alpha/gamma Dual Agonist.,Honda A, Kamata S, Satta C, Machida Y, Uchii K, Terasawa K, Nemoto A, Oyama T, Ishii I Biol Pharm Bull. 2021;44(9):1210-1219. doi: 10.1248/bpb.b21-00232. PMID:34471049[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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