4PVO: Crystal Structure Of Vim-2 Metallo-beta-lactamase In Complex With Ml302 And Ml302f

Citation:
Abstract
The use of beta-lactam antibiotics is compromised by resistance, which is provided by beta-lactamases belonging to both metallo (MBL)- and serine (SBL)-beta-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in beta-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including (19)F NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.
PDB ID: 4PVODownload
MMDB ID: 124863
PDB Deposition Date: 2014/3/18
Updated in MMDB: 2014/11
Experimental Method:
x-ray diffraction
Resolution: 1.48  Å
Source Organism:
Similar Structures:
Biological Unit for 4PVO: monomeric; determined by author and by software (PISA)
Molecular Components in 4PVO
Label Count Molecule
Protein (1 molecule)
1
Beta-lactamase Class B Vim-2
Molecule annotation
Chemicals (8 molecules)
1
3
2
1
3
1
4
2
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.