7TL8

1.95A resolution structure of independent phosphoglycerate mutase from S. aureus in complex with a macrocyclic peptide inhibitor (Sa-D3)

Summary for 7TL8

• Entry DOI: 10.2210/pdb7tl8/pdb
• Related PRD ID: PRD_002492
• Descriptor: 2,3-bisphosphoglycerate-independent phosphoglycerate mutase, Peptide Sa-D3, MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: phosphoglycerate mutase, ipglycermide, macrocyclic peptide inhibitors, metal ion binding, isomerase, isomerase-inhibitor complex, isomerase/inhibitor
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 2
• Total formula weight: 59236.56

Authors

Liu, L.,Lovell, S.,Battaile, K.P.,Dranchak, P.,Queme, B.,Aitha, M.,van Neer, R.H.P.,Kimura, H.,Katho, T.,Suga, H.,Inglese, J. (deposition date: 2022-01-18, release date: 2022-08-10, Last modification date: 2023-10-18)

Primary citation

van Neer, R.H.P.,Dranchak, P.K.,Liu, L.,Aitha, M.,Queme, B.,Kimura, H.,Katoh, T.,Battaile, K.P.,Lovell, S.,Inglese, J.,Suga, H.
Serum-Stable and Selective Backbone-N-Methylated Cyclic Peptides That Inhibit Prokaryotic Glycolytic Mutases.
Acs Chem.Biol., 17:2284-2295, 2022

PubMed Abstract: -Methylated amino acids (-MeAAs) are privileged residues of naturally occurring peptides critical to bioactivity. However, discovery from ribosome display is limited by poor incorporation of -methylated amino acids into the nascent peptide chain attributed to a poor EF-Tu affinity for the -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 -MeAAs. We have here devised a "pool-and-split" enrichment strategy using the RaPID display and identified -methylated MCPs against three species of prokaryotic metal-ion-dependent phosphoglycerate mutases. The enriched MCPs reached 57% -methylation with up to three consecutively incorporated -MeAAs, rivaling natural products. Potent nanomolar inhibitors ranging in ortholog selectivity, strongly mediated by -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 -MeAAs with broadened iPGM species selectivity over the original nematode-selective MCPs. Furthermore, the isolation of a novel metal-ion-independent iPGM inhibitor utilizing a phosphoglycerate mimetic mechanism illustrates the diversity of possible chemotypes encoded by the -MeAA MCP library.

PubMed: 35904259
DOI: 10.1021/acschembio.2c00403

Experimental method

X-RAY DIFFRACTION (1.95 Å)