7ly1

From Proteopedia

Crystal structure of Pseudomonas aeruginosa PBP3 in complex with vaborbactam

PDB ID 7ly1

Drag the structure with the mouse to rotate

Structural highlights

7ly1 is a 1 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FTSI_PSEAE Catalyzes cross-linking of the peptidoglycan cell wall at the division septum (By similarity). Binds penicillin (PubMed:20580675).[HAMAP-Rule:MF_02080]^[1]

Publication Abstract from PubMed

Antimicrobial resistance (AMR) mediated by beta-lactamases is the major and leading cause of resistance to penicillins and cephalosporins among Gram-negative bacteria. beta-Lactamases, periplasmic enzymes that are widely distributed in the bacterial world, protect penicillin-binding proteins (PBPs), the major cell wall synthesizing enzymes, from inactivation by beta-lactam antibiotics. Developing novel PBP inhibitors with a non-beta-lactam scaffold could potentially evade this resistance mechanism. Based on the structural similarities between the evolutionary related serine beta-lactamases and PBPs, we investigated whether the potent beta-lactamase inhibitor, vaborbactam, could also form an acyl-enzyme complex with Pseudomonas aeruginosa PBP3. We found that this cyclic boronate, vaborbactam, inhibited PBP3 (IC50 of 262 muM), and its binding to PBP3 increased the protein thermal stability by about 2 degrees C. Crystallographic analysis of the PBP3:vaborbactam complex reveals that vaborbactam forms a covalent bond with the catalytic S294. The amide moiety of vaborbactam hydrogen bonds with N351 and the backbone oxygen of T487. The carboxyl group of vaborbactam hydrogen bonds with T487, S485, and S349. The thiophene ring and cyclic boronate ring of vaborbactam form hydrophobic interactions, including with V333 and Y503. The active site of the vaborbactam-bound PBP3 harbors the often observed ligand-induced formation of the aromatic wall and hydrophobic bridge, yet the residues involved in this wall and bridge display much higher temperature factors compared to PBP3 structures bound to high-affinity beta-lactams. These insights could form the basis for developing more potent novel cyclic boronate-based PBP inhibitors to inhibit these targets and overcome beta-lactamases-mediated resistance mechanisms.

Structural analysis of the boronic acid beta-lactamase inhibitor vaborbactam binding to Pseudomonas aeruginosa penicillin-binding protein 3.,Kumar V, Viviani SL, Ismail J, Agarwal S, Bonomo RA, van den Akker F PLoS One. 2021 Oct 15;16(10):e0258359. doi: 10.1371/journal.pone.0258359., eCollection 2021. PMID:34653211^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ de Leon SR, Daniels K, Clarke AJ. Production and purification of the penicillin-binding protein 3 from Pseudomonas aeruginosa. Protein Expr Purif. 2010 Oct;73(2):177-83. doi: 10.1016/j.pep.2010.05.005. Epub, 2010 May 16. PMID:20580675 doi:http://dx.doi.org/10.1016/j.pep.2010.05.005
↑ Kumar V, Viviani SL, Ismail J, Agarwal S, Bonomo RA, van den Akker F. Structural analysis of the boronic acid β-lactamase inhibitor vaborbactam binding to Pseudomonas aeruginosa penicillin-binding protein 3. PLoS One. 2021 Oct 15;16(10):e0258359. PMID:34653211 doi:10.1371/journal.pone.0258359