4AWZ

Crystal Structure of the Mobile Metallo-beta-Lactamase AIM-1 from Pseudomonas aeruginosa: Insights into Antibiotic Binding and the role of Gln157

Summary for 4AWZ

• Entry DOI: 10.2210/pdb4awz/pdb
• Related: 4AWY 4AX0 4AX1
• Descriptor: METALLO-BETA-LACTAMASE AIM-1, CALCIUM ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: hydrolase, antibiotic resistance, acquired b3, drug binding site
• Biological source: PSEUDOMONAS AERUGINOSA
• Total number of polymer chains: 3
• Total formula weight: 96345.37

Authors

Leiros, H.-K.S.,Borra, P.S.,Brandsdal, B.O.,Edvardsen, K.S.W.,Spencer, J.,Walsh, T.R.,Samuelsen, O. (deposition date: 2012-06-06, release date: 2012-06-20, Last modification date: 2012-08-15)

Primary citation

Leiros, H.-K.S.,Borra, P.S.,Brandsdal, B.O.,Edvardsen, K.S.W.,Spencer, J.,Walsh, T.R.,Samuelsen, O.
Crystal Structure of the Mobile Metallo-Beta-Lactamase Aim-1 from Pseudomonas Aeruginosa: Insights Into Antibiotic Binding and the Role of Gln157.
Antimicrob.Agents Chemother., 56:4341-, 2012

PubMed Abstract: Metallo-β-lactamase (MBL) genes confer resistance to virtually all β-lactam antibiotics and are rapidly disseminated by mobile genetic elements in Gram-negative bacteria. MBLs belong to three different subgroups, B1, B2, and B3, with the mobile MBLs largely confined to subgroup B1. The B3 MBLs are a divergent subgroup of predominantly chromosomally encoded enzymes. AIM-1 (Adelaide IMipenmase 1) from Pseudomonas aeruginosa was the first B3 MBL to be identified on a readily mobile genetic element. Here we present the crystal structure of AIM-1 and use in silico docking and quantum mechanics and molecular mechanics (QM/MM) calculations, together with site-directed mutagenesis, to investigate its interaction with β-lactams. AIM-1 adopts the characteristic αβ/βα sandwich fold of MBLs but differs from other B3 enzymes in the conformation of an active site loop (residues 156 to 162) which is involved both in disulfide bond formation and, we suggest, interaction with substrates. The structure, together with docking and QM/MM calculations, indicates that the AIM-1 substrate binding site is narrower and more restricted than those of other B3 MBLs, possibly explaining its higher catalytic efficiency. The location of Gln157 adjacent to the AIM-1 zinc center suggests a role in drug binding that is supported by our in silico studies. However, replacement of this residue by either Asn or Ala resulted in only modest reductions in AIM-1 activity against the majority of β-lactam substrates, indicating that this function is nonessential. Our study reveals AIM-1 to be a subclass B3 MBL with novel structural and mechanistic features.

PubMed: 22664968
DOI: 10.1128/AAC.00448-12

Experimental method

X-RAY DIFFRACTION (1.8 Å)