4k8b: Difference between revisions
New page: '''Unreleased structure''' The entry 4k8b is ON HOLD Authors: Nar, H. Description: Crystal structure of HCV NS3/4A protease complexed with inhibitor |
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==Crystal structure of HCV NS3/4A protease complexed with inhibitor== | |||
<StructureSection load='4k8b' size='340' side='right'caption='[[4k8b]], [[Resolution|resolution]] 2.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4k8b]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepacivirus_C Hepacivirus C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K8B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K8B 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]] 2.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RR:N-(TERT-BUTYLCARBAMOYL)-3-METHYL-L-VALYL-(4R)-N-[(1R,2S)-1-CARBOXY-2-ETHENYLCYCLOPROPYL]-4-[(7-METHOXY-2-PHENYLQUINOLIN-4-YL)OXY]-L-PROLINAMIDE'>1RR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4k8b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k8b OCA], [https://pdbe.org/4k8b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k8b RCSB], [https://www.ebi.ac.uk/pdbsum/4k8b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k8b ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q0ZNA6_9HEPC Q0ZNA6_9HEPC] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A ligand-focused strategy employed NMR, X-ray, modeling, and medicinal chemistry to expose the critical role that bioactive conformation played in the design of a variety of drugs that target the HCV protease. The bioactive conformation (bound states) were determined for key inhibitors identified along our drug discovery pathway from the hit to clinical compounds. All adopt similar bioactive conformations for the common core derived from the hit peptide DDIVPC. A carefully designed SAR analysis, based on the advanced inhibitor 1 in which the P1 to P3 side chains and the N-terminal Boc were sequentially truncated, revealed a correlation between affinity and the relative predominance of the bioactive conformation in the free state. Interestingly, synergistic conformation effects on potency were also noted. Comparisons with clinical and recently marketed drugs from the pharmaceutical industry showed that all have the same core and similar bioactive conformations. This suggested that the variety of appendages discovered for these compounds also properly satisfy the bioactive conformation requirements and allowed for a large variety of HCV protease drug candidates to be designed. | |||
Ligand bioactive conformation plays a critical role in the design of drugs that target the hepatitis C virus NS3 protease.,Laplante SR, Nar H, Lemke CT, Jakalian A, Aubry N, Kawai SH J Med Chem. 2014 Mar 13;57(5):1777-89. doi: 10.1021/jm401338c. Epub 2013 Nov 8. PMID:24144444<ref>PMID:24144444</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4k8b" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Nonstructural protein 3D structures|Nonstructural protein 3D structures]] | |||
*[[Virus protease 3D structures|Virus protease 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Hepacivirus C]] | |||
[[Category: Large Structures]] | |||
[[Category: Nar H]] | |||
Latest revision as of 17:28, 8 November 2023
Crystal structure of HCV NS3/4A protease complexed with inhibitorCrystal structure of HCV NS3/4A protease complexed with inhibitor
Structural highlights
FunctionPublication Abstract from PubMedA ligand-focused strategy employed NMR, X-ray, modeling, and medicinal chemistry to expose the critical role that bioactive conformation played in the design of a variety of drugs that target the HCV protease. The bioactive conformation (bound states) were determined for key inhibitors identified along our drug discovery pathway from the hit to clinical compounds. All adopt similar bioactive conformations for the common core derived from the hit peptide DDIVPC. A carefully designed SAR analysis, based on the advanced inhibitor 1 in which the P1 to P3 side chains and the N-terminal Boc were sequentially truncated, revealed a correlation between affinity and the relative predominance of the bioactive conformation in the free state. Interestingly, synergistic conformation effects on potency were also noted. Comparisons with clinical and recently marketed drugs from the pharmaceutical industry showed that all have the same core and similar bioactive conformations. This suggested that the variety of appendages discovered for these compounds also properly satisfy the bioactive conformation requirements and allowed for a large variety of HCV protease drug candidates to be designed. Ligand bioactive conformation plays a critical role in the design of drugs that target the hepatitis C virus NS3 protease.,Laplante SR, Nar H, Lemke CT, Jakalian A, Aubry N, Kawai SH J Med Chem. 2014 Mar 13;57(5):1777-89. doi: 10.1021/jm401338c. Epub 2013 Nov 8. PMID:24144444[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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