1tkr
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Human Dipeptidyl Peptidase IV/CD26 inhibited with Diisopropyl FluoroPhosphate
OverviewOverview
Human dipeptidyl peptidase IV (DPP-IV) is a ubiquitously expressed type II, transmembrane serine protease. It cleaves the penultimate positioned, prolyl bonds at the N terminus of physiologically important peptides such, as the incretin hormones glucagon-like peptide 1 and glucose-dependent, insulinotropic peptide. In this study, we have characterized different, active site mutants. The Y547F mutant as well as the catalytic triad, mutants S630A, D708A, and H740L showed less than 1% wild type activity., X-ray crystal structure analysis of the Y547F mutant revealed no overall, changes compared with wild type apoDPP-IV, except the ablation of the, hydroxyl group of Tyr(547) and a water molecule positioned in close, proximity to Tyr(547). To elucidate further the reaction mechanism, we, determined the crystal structure of DPP-IV in complex with diisopropyl, fluorophosphate, mimicking the tetrahedral intermediate. The kinetic and, structural findings of the tyrosine residue are discussed in relation to, the catalytic mechanism of DPP-IV and to the inhibitory mechanism of the, 2-cyanopyrrolidine class of potent DPP-IV inhibitors, proposing an, explanation for the specificity of this class of inhibitors for the S9b, family among serine proteases.
About this StructureAbout this Structure
1TKR is a Single protein structure of sequence from Homo sapiens with NAG and DFP as ligands. Active as Dipeptidyl-peptidase IV, with EC number 3.4.14.5 Full crystallographic information is available from OCA.
ReferenceReference
Tyrosine 547 constitutes an essential part of the catalytic mechanism of dipeptidyl peptidase IV., Bjelke JR, Christensen J, Branner S, Wagtmann N, Olsen C, Kanstrup AB, Rasmussen HB, J Biol Chem. 2004 Aug 13;279(33):34691-7. Epub 2004 Jun 2. PMID:15175333
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