4F78

Crystal Structure of Vancomycin Resistance D,D-dipeptidase VanXYg

Summary for 4F78

• Entry DOI: 10.2210/pdb4f78/pdb
• Related: 4MUQ 4MUR 4MUS 4MUT 4OAK
• Descriptor: D,D-dipeptidase/D,D-carboxypeptidase, ZINC ION, CHLORIDE ION, ... (7 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, vancomycin resistance, d-alanine-d-alanine, hydrolase
• Biological source: Enterococcus faecalis
• Total number of polymer chains: 1
• Total formula weight: 30869.83

Authors

Stogios, P.J.,Wawrzak, Z.,Evdokimova, E.,Minasov, G.,Egorova, O.,Di Leo, R.,Kudritska, M.,Yim, V.,Meziane-Cherif, D.,Courvalin, P.,Savchenko, A.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2012-05-15, release date: 2012-05-23, Last modification date: 2014-05-14)

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 (1.95 Å)