PDBsum entry 4muq

Hydrolase

PDB id: 4muq

Contents

Protein chain

251 a.a.

Ligands

LY0-2D8

EDO

GOL ×2

PE3 ×4

Metals

_ZN

Waters ×294

PDB id:

4muq

Name:

Hydrolase

Title:

Crystal structure of vancomycin resistance d,d-dipeptidase vanxyg in complex with d-ala-d-ala phosphinate analog

Structure:

D,d-dipeptidase/d,d-carboxypeptidase. Chain: a. Fragment: vanxyg. Synonym: d,d-peptidase, vanxyg. Engineered: yes

Source:

Enterococcus faecalis. Organism_taxid: 1351. Strain: bm4518. Gene: vanxyg, vanyg2. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.36Å R-factor: 0.163 R-free: 0.185

Authors:

P.J.Stogios,E.Evdokimova,D.Meziane-Cherif,R.Di Leo,V.Yim,P.Courvalin, A.Savchenko,W.F.Anderson,Center For Structural Genomics Of Infectious Diseases (Csgid)

Key ref:

D.Meziane-Cherif et al. (2014). Structural basis for the evolution of vancomycin resistance D,D-peptidases. Proc Natl Acad Sci U S A, 111, 5872-5877. PubMed id: 24711382 DOI: 10.1073/pnas.1402259111

Date:

23-Sep-13 Release date: 09-Oct-13

Protein chain

Q9KHL8  (Q9KHL8_ENTFL) -  D,D-dipeptidase/D,D-carboxypeptidase from Enterococcus faecalis

Seq: 254 a.a.

Struc: 251 a.a.

DOI no: 10.1073/pnas.1402259111

Proc Natl Acad Sci U S A 111:5872-5877 (2014)

PubMed id: 24711382

Structural basis for the evolution of vancomycin resistance D,D-peptidases.

D.Meziane-Cherif, P.J.Stogios, E.Evdokimova, A.Savchenko, P.Courvalin.

ABSTRACT

Vancomycin resistance in Gram-positive bacteria is due to production of cell-wall precursors ending in d-Ala-d-Lac or d-Ala-d-Ser, to which vancomycin exhibits low binding affinities, and to the elimination of the high-affinity precursors ending in d-Ala-d-Ala. Depletion of the susceptible high-affinity precursors is catalyzed by the zinc-dependent d,d-peptidases VanX and VanY acting on dipeptide (d-Ala-d-Ala) or pentapeptide (UDP-MurNac-l-Ala-d-Glu-l-Lys-d-Ala-d-Ala), respectively. Some of the vancomycin resistance operons encode VanXY d,d-carboxypeptidase, which hydrolyzes both di- and pentapeptide. The molecular basis for the diverse specificity of Van d,d-peptidases remains unknown. We present the crystal structures of VanXYC and VanXYG in apo and transition state analog-bound forms and of VanXYC in complex with the d-Ala-d-Ala substrate and d-Ala product. Structural and biochemical analysis identified the molecular determinants of VanXY dual specificity. VanXY residues 110-115 form a mobile cap over the catalytic site, whose flexibility is involved in the switch between di- and pentapeptide hydrolysis. Structure-based alignment of the Van d,d-peptidases showed that VanY enzymes lack this element, which promotes binding of the penta- rather than that of the dipeptide. The structures also highlight the molecular basis for selection of d-Ala-ending precursors over the modified resistance targets. These results illustrate the remarkable adaptability of the d,d-peptidase fold in response to antibiotic pressure via evolution of specific structural elements that confer hydrolytic activity against vancomycin-susceptible peptidoglycan precursors.