1Z6F

Crystal structure of penicillin-binding protein 5 from E. coli in complex with a boronic acid inhibitor

Summary for 1Z6F

• Entry DOI: 10.2210/pdb1z6f/pdb
• Related: 1NJ4 1NZO 1NZU 1SDN
• Descriptor: Penicillin-binding protein 5, N1-[(1R)-1-(DIHYDROXYBORYL)ETHYL]-N2-[(TERT-BUTOXYCARBONYL)-D-GAMMA-GLUTAMYL]-N6-[(BENZYLOXY)CARBONYL-L-LYSINAMIDE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: peptidoglycan synthesis, penicillin-binding protein, dd-carboxypeptidase, hydrolase, boronic acid
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 40513.65

Authors

Nicola, G.,Peddi, S.,Stefanova, M.,Nicholas, R.A.,Gutheil, W.G.,Davies, C. (deposition date: 2005-03-22, release date: 2005-06-21, Last modification date: 2023-08-23)

Primary citation

Nicola, G.,Peddi, S.,Stefanova, M.,Nicholas, R.A.,Gutheil, W.G.,Davies, C.
Crystal Structure of Escherichia coli Penicillin-Binding Protein 5 Bound to a Tripeptide Boronic Acid Inhibitor: A Role for Ser-110 in Deacylation.
Biochemistry, 44:8207-8217, 2005

PubMed Abstract: Penicillin-binding protein 5 (PBP 5) from Escherichia coli is a well-characterized d-alanine carboxypeptidase that serves as a prototypical enzyme to elucidate the structure, function, and catalytic mechanism of PBPs. A comprehensive understanding of the catalytic mechanism underlying d-alanine carboxypeptidation and antibiotic binding has proven elusive. In this study, we report the crystal structure at 1.6 A resolution of PBP 5 in complex with a substrate-like peptide boronic acid, which was designed to resemble the transition-state intermediate during the deacylation step of the enzyme-catalyzed reaction with peptide substrates. In the structure of the complex, the boron atom is covalently attached to Ser-44, which in turn is within hydrogen-bonding distance to Lys-47. This arrangement further supports the assignment of Lys-47 as the general base that activates Ser-44 during acylation. One of the two hydroxyls in the boronyl center (O2) is held by the oxyanion hole comprising the amides of Ser-44 and His-216, while the other hydroxyl (O3), which is analogous to the nucleophilic water for hydrolysis of the acyl-enzyme intermediate, is solvated by a water molecule that bridges to Ser-110. Lys-47 is not well-positioned to act as the catalytic base in the deacylation reaction. Instead, these data suggest a mechanism of catalysis for deacylation that uses a hydrogen-bonding network, involving Lys-213, Ser-110, and a bridging water molecule, to polarize the hydrolytic water molecule.

PubMed: 15938610
DOI: 10.1021/bi0473004

Experimental method

X-RAY DIFFRACTION (1.6 Å)