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<StructureSection load='5ta2' size='340' side='right'caption='[[5ta2]], [[Resolution|resolution]] 1.48&Aring;' scene=''>
<StructureSection load='5ta2' size='340' side='right'caption='[[5ta2]], [[Resolution|resolution]] 1.48&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5ta2]] is a 1 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=5TA2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5TA2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5ta2]] 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=5TA2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TA2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=78X:11-[(3-HYDROXYPHENYL)METHYL]-18-METHOXY-2,17-DIMETHYL-14-(PROPAN-2-YL)-3-OXA-9,12,15,28-TETRAAZATRICYCLO[21.3.1.1~5,9~]OCTACOSA-1(27),21,23,25-TETRAENE-4,10,13,16-TETRONE'>78X</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]] 1.48&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5t9u|5t9u]], [[5t9w|5t9w]], [[5t9z|5t9z]], [[5ta4|5ta4]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=78X:11-[(3-HYDROXYPHENYL)METHYL]-18-METHOXY-2,17-DIMETHYL-14-(PROPAN-2-YL)-3-OXA-9,12,15,28-TETRAAZATRICYCLO[21.3.1.1~5,9~]OCTACOSA-1(27),21,23,25-TETRAENE-4,10,13,16-TETRONE'>78X</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPIA, CYPA ([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=5ta2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta2 OCA], [https://pdbe.org/5ta2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ta2 RCSB], [https://www.ebi.ac.uk/pdbsum/5ta2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta2 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://proteopedia.org/fgij/fg.htm?mol=5ta2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ta2 OCA], [http://pdbe.org/5ta2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ta2 RCSB], [http://www.ebi.ac.uk/pdbsum/5ta2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ta2 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PPIA_HUMAN PPIA_HUMAN]] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.  
[https://www.uniprot.org/uniprot/PPIA_HUMAN PPIA_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a pi-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold, to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.
 
Discovery of Potent Cyclophilin Inhibitors based on Structural Simplification of Sanglifehrin A.,Steadman VA, Pettit SB, Poullennec KG, Lazarides L, Keats AJ, Dean DK, Stanway SJ, Austin CA, Sanvoisin JA, Watt GM, Fliri HG, Liclican AC, Jin D, Wong MH, Leavitt SA, Lee YJ, Tian Y, Frey CR, Appleby TC, Schmitz U, Jansa P, Mackman RL, Schultz BE J Med Chem. 2017 Jan 11. doi: 10.1021/acs.jmedchem.6b01329. PMID:28075591<ref>PMID:28075591</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ta2" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Cyclophilin 3D structures|Cyclophilin 3D structures]]
*[[Cyclophilin 3D structures|Cyclophilin 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Peptidylprolyl isomerase]]
[[Category: Appleby TC]]
[[Category: Appleby, T C]]
[[Category: Mackman RL]]
[[Category: Mackman, R L]]
[[Category: Pettit S]]
[[Category: Pettit, S]]
[[Category: Schmitz U]]
[[Category: Schmitz, U]]
[[Category: Schultz B]]
[[Category: Schultz, B]]
[[Category: Steadman V]]
[[Category: Steadman, V]]
[[Category: Cyclophilin inhibitor antiviral hcv]]
[[Category: Isomerase-isomerase inhibitor complex]]

Latest revision as of 14:19, 6 March 2024

Discovery of a Potent Cyclophilin Inhibitor (Compound 7) based on Structural Simplification of Sanglifehrin A

5ta2, resolution 1.48Å

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