PDBsum entry 6pc5

Ribosome

PDB id: 6pc5

Contents

Protein chains

271 a.a.

144 a.a.

201 a.a.

206 a.a.

142 a.a.

DNA/RNA

Ligands

MHW-THR-DBB-PRO-MEA-MHV-004

O7V

PDB id:

6pc5

Name:

Ribosome

Title:

E. Coli 50s ribosome bound to compounds 46 and vs1

Structure:

23s ribosomal RNA. Chain: i. 5s ribosomal RNA. Chain: j. 50s ribosomal protein l2. Chain: k. Synonym: large ribosomal subunit protein ul2. 50s ribosomal protein l15. Chain: l.

Source:

Escherichia coli. Organism_taxid: 562. Streptomyces virginiae. Organism_taxid: 1961

Authors:

J.Pellegrino,D.J.Lee,J.S.Fraser,I.B.Seiple

Key ref:

Q.Li et al. (2020). Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature, 586, 145-150. PubMed id: 32968273 DOI: 10.1038/s41586-020-2761-3

Date:

16-Jun-19 Release date: 17-Jun-20

Protein chain

P60422  (RL2_ECOLI) -  Large ribosomal subunit protein uL2 from Escherichia coli (strain K12)

Seq: 273 a.a.

Struc: 271 a.a.

Protein chain

A0A037Y8L6  () -  Large ribosomal subunit protein uL15 from Escherichia coli

Seq: 144 a.a.

Struc: 144 a.a.

Protein chain

D7Z9F6  (D7Z9F6_ECOLX) -

Protein chain

P60438  (RL3_ECOLI) -  Large ribosomal subunit protein uL3 from Escherichia coli (strain K12)

Seq: 209 a.a.

Struc: 206 a.a.

Protein chain

D7ZET0  (D7ZET0_ECOLX) -

DNA/RNA chains

G-G-U-U-A-A-G-C-G-A-C-U-A-A-G-C-G-U-A-C-A-C-G-G-U-G-G-A-U-G-C-C-C-U-G-G-C-A-G- ... 2897 bases

G-C-C-U-G-G-C-G-G-C-C-G-U-A-G-C-G-C-G-G-U-G-G-U-C-C-C-A-C-C-U-G-A-C-C-C-C-A-U- 118 bases

DOI no: 10.1038/s41586-020-2761-3

Nature 586:145-150 (2020)

PubMed id: 32968273

Synthetic group A streptogramin antibiotics that overcome Vat resistance.

Q.Li, J.Pellegrino, D.J.Lee, A.A.Tran, H.A.Chaires, R.Wang, J.E.Park, K.Ji, D.Chow, N.Zhang, A.F.Brilot, J.T.Biel, G.van Zundert, K.Borrelli, D.Shinabarger, C.Wolfe, B.Murray, M.P.Jacobson, E.Mühle, O.Chesneau, J.S.Fraser, I.B.Seiple.

ABSTRACT

Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics¹. Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins², potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome³. Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed². Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms.