Crystal structure of human renal dipeptidase involved in beta-lactam hydrolysis.
Human renal dipeptidase is a membrane-bound glycoprotein hydrolyzing dipeptides and is involved in hydrolytic metabolism of penem and carbapenem beta-lactam antibiotics. The crystal structures of the saccharide-trimmed enzyme are determined as unliganded and inhibitor-liganded forms. They are informative for designing new antibiotics that are not hydrolyzed by this enzyme. The active site in each of the (alpha/beta)(8) barrel subunits of the homodimeric molecule is composed of binuclear zinc ions bridged by the Glu125 side-chain located at the bottom of the barrel, and it faces toward the microvillar membrane of a kidney tubule. A dipeptidyl moiety of the therapeutically used cilastatin inhibitor is fully accommodated in the active-site pocket, which is small enough for precise recognition of dipeptide substrates. The barrel and active-site architectures utilizing catalytic metal ions exhibit unexpected similarities to those of the murine adenosine deaminase and the catalytic domain of the bacterial urease.
Nitanai
Yasushi
Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. nitanai@spring8.or.jp
Satow
Yoshinori
Y
Adachi
Hideki
H
Tsujimoto
Masafumi
M
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D004150:Dipeptidases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D004150:Dipeptidases; C038937:dipeptidase