PDBsum entry 4e3m

Hydrolase/hydrolase inhibitor

PDB id: 4e3m

Contents

Protein chains

358 a.a.

Ligands

0ND ×3

PO4 ×2

Waters ×577

PDB id:

4e3m

Name:

Hydrolase/hydrolase inhibitor

Title:

Crystal structure of ampc beta-lactamase in complex with a 2-chloro-4- tetrazolyl benzene sulfonamide boronic acid inhibitor

Structure:

Beta-lactamase. Chain: a, b. Synonym: cephalosporinase. Engineered: yes

Source:

Escherichia coli. Organism_taxid: 83333. Strain: k12. Gene: ampa, ampc, b4150, jw4111. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.44Å R-factor: 0.162 R-free: 0.193

Authors:

O.Eidam,B.K.Shoichet

Key ref:

O.Eidam et al. (2012). Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo. Proc Natl Acad Sci U S A, 109, 17448-17453. PubMed id: 23043117

Date:

09-Mar-12 Release date: 26-Sep-12

Protein chains

P00811  (AMPC_ECOLI) -  Beta-lactamase from Escherichia coli (strain K12)

Seq: 377 a.a.

Struc: 358 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: a beta-lactam + H2O = a substituted beta-amino acid
• Cofactor: Zn(2+)

Proc Natl Acad Sci U S A 109:17448-17453 (2012)

PubMed id: 23043117

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo.

O.Eidam, C.Romagnoli, G.Dalmasso, S.Barelier, E.Caselli, R.Bonnet, B.K.Shoichet, F.Prati.

ABSTRACT

Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K(i) of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.