4MUR

Crystal structure of vancomycin resistance D,D-dipeptidase/D,D-pentapeptidase VanXYc D59S mutant

Summary for 4MUR

• Entry DOI: 10.2210/pdb4mur/pdb
• Related: 4F78 4MUQ 4MUS 4MUT 4OAK
• Descriptor: D,D-dipeptidase/D,D-carboxypeptidase, ZINC ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: center for structural genomics of infectious diseases, csgid, national institute of allergy and infectious diseases, niaid, alpha+beta protein, metallopeptidase, hedgehog/dd-peptidase fold, merops m15b subfamily, zn2+-dependent d, d-dipeptidase, d-pentapeptidase, vancomycin resistance, antibiotic resistance, hydrolase
• Biological source: Enterococcus gallinarum
• Total number of polymer chains: 2
• Total formula weight: 52510.51

Authors

Stogios, P.J.,Evdokimova, E.,Meziane-Cherif, D.,Di Leo, R.,Yim, V.,Courvalin, P.,Savchenko, A.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2013-09-23, release date: 2013-10-02, Last modification date: 2023-09-20)

Primary citation

Meziane-Cherif, D.,Stogios, P.J.,Evdokimova, E.,Savchenko, A.,Courvalin, P.
Structural basis for the evolution of vancomycin resistance D,D-peptidases.
Proc.Natl.Acad.Sci.USA, 111:5872-5877, 2014

PubMed 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.

PubMed: 24711382
DOI: 10.1073/pnas.1402259111

Experimental method

X-RAY DIFFRACTION (1.65 Å)