Event Title
A Class D Beta-lactamase Clinical Variant with Activity Against Carbapenems, Ceftazidime, and Aztreonam
Presentation Type
Poster/Portfolio
Presenter Major(s)
Chemistry
Mentor Information
David Leonard
Department
Chemistry
Location
Kirkhof Center KC41
Start Date
10-4-2013 11:00 AM
End Date
10-4-2013 12:00 PM
Keywords
Health, Life Science
Abstract
Like all known class D carbapenemases, OXA-23 cannot bind or hydrolyze the cephalosporin ceftazidime. OXA-146 is an OXA-23 subfamily clinical variant that differs from the parent enzyme by an alanine duplication in the loop connecting beta-strands b5 and b6. We have discovered that this insertion enables OXA-146 to bind and hydrolyze ceftazidime with efficiency comparable to other extended spectrum class D beta-lactamases. In this study, we report the crystal structures of both the OXA-23 and OXA-146 enzymes. A comparison of the two structures shows that the extra alanine moves a methionine out of its normal position where it forms a bridge over the top of the active site. The insertion also lengthens the b5-b6 loop, moving its main-chain atoms further away from the active site. A model of ceftazidime bound in the active site shows that these two structural alterations are both likely to relieve steric clashes between the bulky R1 side-chain of ceftazidime and OXA-23.
A Class D Beta-lactamase Clinical Variant with Activity Against Carbapenems, Ceftazidime, and Aztreonam
Kirkhof Center KC41
Like all known class D carbapenemases, OXA-23 cannot bind or hydrolyze the cephalosporin ceftazidime. OXA-146 is an OXA-23 subfamily clinical variant that differs from the parent enzyme by an alanine duplication in the loop connecting beta-strands b5 and b6. We have discovered that this insertion enables OXA-146 to bind and hydrolyze ceftazidime with efficiency comparable to other extended spectrum class D beta-lactamases. In this study, we report the crystal structures of both the OXA-23 and OXA-146 enzymes. A comparison of the two structures shows that the extra alanine moves a methionine out of its normal position where it forms a bridge over the top of the active site. The insertion also lengthens the b5-b6 loop, moving its main-chain atoms further away from the active site. A model of ceftazidime bound in the active site shows that these two structural alterations are both likely to relieve steric clashes between the bulky R1 side-chain of ceftazidime and OXA-23.