7tl8: Difference between revisions
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==1.95A resolution structure of independent phosphoglycerate mutase from S. aureus in complex with a macrocyclic peptide inhibitor (Sa-D3)== | |||
<StructureSection load='7tl8' size='340' side='right'caption='[[7tl8]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7tl8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus] 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=7TL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TL8 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]] 1.95Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5JP:N-METHYL-L-SERINE'>5JP</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=DTY:D-TYROSINE'>DTY</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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=7tl8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tl8 OCA], [https://pdbe.org/7tl8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tl8 RCSB], [https://www.ebi.ac.uk/pdbsum/7tl8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tl8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/W8U5L7_STAAU W8U5L7_STAAU] Catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglycerate.[HAMAP-Rule:MF_01038] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
N-Methylated amino acids (N-MeAAs) are privileged residues of naturally occurring peptides critical to bioactivity. However, de novo discovery from ribosome display is limited by poor incorporation of N-methylated amino acids into the nascent peptide chain attributed to a poor EF-Tu affinity for the N-methyl-aminoacyl-tRNA. By reconfiguring the tRNA's T-stem region to compensate and tune the EF-Tu affinity, we conducted Random nonstandard Peptides Integrated Discovery (RaPID) display of a macrocyclic peptide (MCP) library containing six different N-MeAAs. We have here devised a "pool-and-split" enrichment strategy using the RaPID display and identified N-methylated MCPs against three species of prokaryotic metal-ion-dependent phosphoglycerate mutases. The enriched MCPs reached 57% N-methylation with up to three consecutively incorporated N-MeAAs, rivaling natural products. Potent nanomolar inhibitors ranging in ortholog selectivity, strongly mediated by N-methylation, were identified. Co-crystal structures reveal an architecturally related Ce-2 Ipglycermide active-site metal-ion-coordinating Cys lariat MCP, functionally dependent on two cis N-MeAAs with broadened iPGM species selectivity over the original nematode-selective MCPs. Furthermore, the isolation of a novel metal-ion-independent Staphylococcus aureus iPGM inhibitor utilizing a phosphoglycerate mimetic mechanism illustrates the diversity of possible chemotypes encoded by the N-MeAA MCP library. | |||
Serum-Stable and Selective Backbone-N-Methylated Cyclic Peptides That Inhibit Prokaryotic Glycolytic Mutases.,van Neer RHP, Dranchak PK, Liu L, Aitha M, Queme B, Kimura H, Katoh T, Battaile KP, Lovell S, Inglese J, Suga H ACS Chem Biol. 2022 Aug 19;17(8):2284-2295. doi: 10.1021/acschembio.2c00403. Epub, 2022 Jul 29. PMID:35904259<ref>PMID:35904259</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7tl8" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: Battaile | *[[Phosphoglycerate mutase 3D structures|Phosphoglycerate mutase 3D structures]] | ||
[[Category: Dranchak | == References == | ||
[[Category: | <references/> | ||
[[Category: Katho | __TOC__ | ||
[[Category: Lovell | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Staphylococcus aureus]] | ||
[[Category: | [[Category: Synthetic construct]] | ||
[[Category: Aitha M]] | |||
[[Category: Battaile KP]] | |||
[[Category: Dranchak P]] | |||
[[Category: Inglese J]] | |||
[[Category: Katho T]] | |||
[[Category: Kimura H]] | |||
[[Category: Liu L]] | |||
[[Category: Lovell S]] | |||
[[Category: Queme B]] | |||
[[Category: Suga H]] | |||
[[Category: Van Neer RHP]] | |||
Latest revision as of 20:05, 18 October 2023
1.95A resolution structure of independent phosphoglycerate mutase from S. aureus in complex with a macrocyclic peptide inhibitor (Sa-D3)1.95A resolution structure of independent phosphoglycerate mutase from S. aureus in complex with a macrocyclic peptide inhibitor (Sa-D3)
Structural highlights
FunctionW8U5L7_STAAU Catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglycerate.[HAMAP-Rule:MF_01038] Publication Abstract from PubMedN-Methylated amino acids (N-MeAAs) are privileged residues of naturally occurring peptides critical to bioactivity. However, de novo discovery from ribosome display is limited by poor incorporation of N-methylated amino acids into the nascent peptide chain attributed to a poor EF-Tu affinity for the N-methyl-aminoacyl-tRNA. By reconfiguring the tRNA's T-stem region to compensate and tune the EF-Tu affinity, we conducted Random nonstandard Peptides Integrated Discovery (RaPID) display of a macrocyclic peptide (MCP) library containing six different N-MeAAs. We have here devised a "pool-and-split" enrichment strategy using the RaPID display and identified N-methylated MCPs against three species of prokaryotic metal-ion-dependent phosphoglycerate mutases. The enriched MCPs reached 57% N-methylation with up to three consecutively incorporated N-MeAAs, rivaling natural products. Potent nanomolar inhibitors ranging in ortholog selectivity, strongly mediated by N-methylation, were identified. Co-crystal structures reveal an architecturally related Ce-2 Ipglycermide active-site metal-ion-coordinating Cys lariat MCP, functionally dependent on two cis N-MeAAs with broadened iPGM species selectivity over the original nematode-selective MCPs. Furthermore, the isolation of a novel metal-ion-independent Staphylococcus aureus iPGM inhibitor utilizing a phosphoglycerate mimetic mechanism illustrates the diversity of possible chemotypes encoded by the N-MeAA MCP library. Serum-Stable and Selective Backbone-N-Methylated Cyclic Peptides That Inhibit Prokaryotic Glycolytic Mutases.,van Neer RHP, Dranchak PK, Liu L, Aitha M, Queme B, Kimura H, Katoh T, Battaile KP, Lovell S, Inglese J, Suga H ACS Chem Biol. 2022 Aug 19;17(8):2284-2295. doi: 10.1021/acschembio.2c00403. Epub, 2022 Jul 29. PMID:35904259[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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