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==X-Ray structure of a CypA-Alisporivir complex at 1.5 angstrom resolution== | ==X-Ray structure of a CypA-Alisporivir complex at 1.5 angstrom resolution== | ||
<StructureSection load='5hsv' size='340' side='right' caption='[[5hsv]], [[Resolution|resolution]] 1.50Å' scene=''> | <StructureSection load='5hsv' size='340' side='right'caption='[[5hsv]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5hsv]] is a 8 chain structure with sequence from [ | <table><tr><td colspan='2'>[[5hsv]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Chlorocebus_aethiops Chlorocebus aethiops] and [https://en.wikipedia.org/wiki/Tolypocladium_inflatum Tolypocladium inflatum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HSV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HSV FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=66E:N-ethyl-L-valine'>66E</scene>, <scene name='pdbligand=ABA:ALPHA-AMINOBUTYRIC+ACID'>ABA</scene>, <scene name='pdbligand=BMT:4-METHYL-4-[(E)-2-BUTENYL]-4,N-METHYL-THREONINE'>BMT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DAM:N-METHYL-ALPHA-BETA-DEHYDROALANINE'>DAM</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=MVA:N-METHYLVALINE'>MVA</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=5hsv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hsv OCA], [https://pdbe.org/5hsv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hsv RCSB], [https://www.ebi.ac.uk/pdbsum/5hsv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hsv ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/PPIA_CHLAE PPIA_CHLAE] 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 == | |||
Alisporivir (ALV) is an 11-amino-acid hydrophobic cyclic peptide with N-methyl-D-alanine and N-ethyl-L-valine (NEV) residues at positions 3 and 4, respectively. ALV is a non-immunosuppressive cyclosporin A (CsA) derivative. This inhibitor targets cyclophilins (Cyps), a family of proteins with peptidyl-prolyl cis/trans isomerase enzymatic activity. Cyps act as protein chaperones and are involved in numerous cellular functions. Moreover, Cyps have been shown to be an essential cofactor for the replication of many viruses, including Hepatitis C virus and Human immunodeficiency virus, and have also been shown to be involved in mitochondrial diseases. For these reasons, cyclophilins represent an attractive drug target. The structure of ALV in complex with cyclophilin A (CypA), the most abundant Cyp in humans, has been determined at 1.5 A resolution. This first structure of the CypA-ALV complex shows that the binding of ALV is highly similar to that of CsA. The high resolution allowed the unambiguous determination of the conformations of residues 3 and 4 in ALV when bound to its target. In particular, the side-chain conformation of NEV4 precludes the interaction of the CypA-ALV complex with calcineurin, a cellular protein phosphatase involved in the immune response, which explains the non-immunosuppressive property of ALV. This study provides detailed molecular insights into the CypA-ALV interaction. | |||
X-ray structure of alisporivir in complex with cyclophilin A at 1.5 A resolution.,Dujardin M, Bouckaert J, Rucktooa P, Hanoulle X Acta Crystallogr F Struct Biol Commun. 2018 Sep 1;74(Pt 9):583-592. doi:, 10.1107/S2053230X18010415. Epub 2018 Sep 3. PMID:30198892<ref>PMID:30198892</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5hsv" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Cyclophilin|Cyclophilin]] | *[[Cyclophilin 3D structures|Cyclophilin 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Chlorocebus aethiops]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Bouckaert | [[Category: Tolypocladium inflatum]] | ||
[[Category: Dujardin | [[Category: Bouckaert J]] | ||
[[Category: Hanoulle | [[Category: Dujardin M]] | ||
[[Category: Rucktooa | [[Category: Hanoulle X]] | ||
[[Category: Rucktooa P]] | |||
Latest revision as of 13:53, 16 August 2023
X-Ray structure of a CypA-Alisporivir complex at 1.5 angstrom resolutionX-Ray structure of a CypA-Alisporivir complex at 1.5 angstrom resolution
Structural highlights
FunctionPPIA_CHLAE PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Publication Abstract from PubMedAlisporivir (ALV) is an 11-amino-acid hydrophobic cyclic peptide with N-methyl-D-alanine and N-ethyl-L-valine (NEV) residues at positions 3 and 4, respectively. ALV is a non-immunosuppressive cyclosporin A (CsA) derivative. This inhibitor targets cyclophilins (Cyps), a family of proteins with peptidyl-prolyl cis/trans isomerase enzymatic activity. Cyps act as protein chaperones and are involved in numerous cellular functions. Moreover, Cyps have been shown to be an essential cofactor for the replication of many viruses, including Hepatitis C virus and Human immunodeficiency virus, and have also been shown to be involved in mitochondrial diseases. For these reasons, cyclophilins represent an attractive drug target. The structure of ALV in complex with cyclophilin A (CypA), the most abundant Cyp in humans, has been determined at 1.5 A resolution. This first structure of the CypA-ALV complex shows that the binding of ALV is highly similar to that of CsA. The high resolution allowed the unambiguous determination of the conformations of residues 3 and 4 in ALV when bound to its target. In particular, the side-chain conformation of NEV4 precludes the interaction of the CypA-ALV complex with calcineurin, a cellular protein phosphatase involved in the immune response, which explains the non-immunosuppressive property of ALV. This study provides detailed molecular insights into the CypA-ALV interaction. X-ray structure of alisporivir in complex with cyclophilin A at 1.5 A resolution.,Dujardin M, Bouckaert J, Rucktooa P, Hanoulle X Acta Crystallogr F Struct Biol Commun. 2018 Sep 1;74(Pt 9):583-592. doi:, 10.1107/S2053230X18010415. Epub 2018 Sep 3. PMID:30198892[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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