PDBsum entry 2y2n

Transferase

PDB id: 2y2n

Contents

Protein chain

468 a.a.

Ligands

E07

Metals

_CL ×22

_NA

Waters ×237

PDB id:

2y2n

Name:

Transferase

Title:

Penicillin-binding protein 1b (pbp-1b) in complex with an alkyl boronate (e07)

Structure:

Penicillin-binding protein 1b. Chain: a. Fragment: transpeptidase domain, residues 101-125,323-791. Synonym: pbp1b. Engineered: yes. Mutation: yes. Other_details: alkyl boronate (e07) covalently bond to s460

Source:

Streptococcus pneumoniae. Organism_taxid: 171101. Strain: r6. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: plys.

Resolution:

2.07Å R-factor: 0.197 R-free: 0.243

Authors:

C.Contreras-Martel,A.Amoroso,E.C.Woon,A.Zervosen,S.Inglis,A.Martins, O.Verlaine,A.Rydzik,V.Job,A.Luxen,B.Joris,C.J.Schofield,A.Dessen

Key ref:

C.Contreras-Martel et al. (2011). Structure-guided design of cell wall biosynthesis inhibitors that overcome β-lactam resistance in Staphylococcus aureus (MRSA). Acs Chem Biol, 6, 943-951. PubMed id: 21732689 DOI: 10.1021/cb2001846

Date:

15-Dec-10 Release date: 03-Aug-11

Protein chain

Q7CRA4  (Q7CRA4_STRR6) -  peptidoglycan glycosyltransferase from Streptococcus pneumoniae (strain ATCC BAA-255 / R6)

Seq: 821 a.a.

Struc: 468 a.a.*

* PDB and UniProt seqs differ at 14 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.4.99.28 - peptidoglycan glycosyltransferase.
• Reaction: [GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)](n)- di-trans,octa-cis-undecaprenyl diphosphate + beta-D-GlcNAc-(1->4)- Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-di-trans,octa- cis-undecaprenyl diphosphate = [GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D- Glu-L-Lys-D-Ala-D-Ala)](n+1)-di-trans,octa-cis-undecaprenyl diphosphate + di-trans,octa-cis-undecaprenyl diphosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1021/cb2001846

Acs Chem Biol 6:943-951 (2011)

PubMed id: 21732689

Structure-guided design of cell wall biosynthesis inhibitors that overcome β-lactam resistance in Staphylococcus aureus (MRSA).

C.Contreras-Martel, A.Amoroso, E.C.Woon, A.Zervosen, S.Inglis, A.Martins, O.Verlaine, A.M.Rydzik, V.Job, A.Luxen, B.Joris, C.J.Schofield, A.Dessen.

ABSTRACT

β-Lactam antibiotics have long been a treatment of choice for bacterial infections since they bind irreversibly to Penicillin-Binding Proteins (PBPs), enzymes that are vital for cell wall biosynthesis. Many pathogens express drug-insensitive PBPs rendering β-lactams ineffective, revealing a need for new types of PBP inhibitors active against resistant strains. We have identified alkyl boronic acids that are active against pathogens including methicillin-resistant S. aureus (MRSA). The crystal structures of PBP1b complexed to 11 different alkyl boronates demonstrate that in vivo efficacy correlates with the mode of inhibitor side chain binding. Staphylococcal membrane analyses reveal that the most potent alkyl boronate targets PBP1, an autolysis system regulator, and PBP2a, a low β-lactam affinity enzyme. This work demonstrates the potential of boronate-based PBP inhibitors for circumventing β-lactam resistance and opens avenues for the development of novel antibiotics that target Gram-positive pathogens.