View source for 7z4s


==Crystal structure of SARS-CoV-2 Mpro in complex with cyclic peptide GM4 including unnatural amino acids.==
<StructureSection load='7z4s' size='340' side='right'caption='[[7z4s]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7z4s]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Z4S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Z4S 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]] 1.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=DTY:D-TYROSINE'>DTY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=II7:3-azanylcyclobutane-1-carboxylic+acid'>II7</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=7z4s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7z4s OCA], [https://pdbe.org/7z4s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7z4s RCSB], [https://www.ebi.ac.uk/pdbsum/7z4s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7z4s ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
gamma-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of gamma-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic gamma(2,4)-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M(pro)). Two kinds of cyclic gamma(2,4)-amino acids, cis-3-aminocyclobutane carboxylic acid (gamma(1)) and (1R,3S)-3-aminocyclopentane carboxylic acid (gamma(2)), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M(pro) inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with gamma(1) at the fourth position, manifests a 5.2 nM dissociation constant. An M(pro):GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The gamma(1) interacts with the S1' catalytic subsite and contributes to a 12-fold increase in proteolytic stability compared to its alanine-substituted variant. Knowledge of interactions between GM4 and M(pro) enabled production of a variant with a 5-fold increase in potency.

In vitro selection of macrocyclic peptide inhibitors containing cyclic gamma(2,4)-amino acids targeting the SARS-CoV-2 main protease.,Miura T, Malla TR, Owen CD, Tumber A, Brewitz L, McDonough MA, Salah E, Terasaka N, Katoh T, Lukacik P, Strain-Damerell C, Mikolajek H, Walsh MA, Kawamura A, Schofield CJ, Suga H Nat Chem. 2023 Jul;15(7):998-1005. doi: 10.1038/s41557-023-01205-1. Epub 2023 May , 22. PMID:37217786<ref>PMID:37217786</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7z4s" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Synthetic construct]]
[[Category: Brewitz L]]
[[Category: Katoh T]]
[[Category: Kawamura A]]
[[Category: Lukacik L]]
[[Category: Malla T]]
[[Category: McDonough MA]]
[[Category: Miura T]]
[[Category: Owen CD]]
[[Category: Salah E]]
[[Category: Schofield CJ]]
[[Category: Strain-Damerell CM]]
[[Category: Suga H]]
[[Category: Terasaka N]]
[[Category: Tumber A]]
[[Category: Walsh MA]]