title: Discovery of non-covalent dipeptidyl peptidase IV inhibitors which induce a conformational change in the active site.
abstract: A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA. SHEEHAN_SCOTT@LILLY.COM
authors.forename: Scott M
authors.initials: SM
authors.lastname: Sheehan
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Mest
authors.forename: Brian M
authors.initials: BM
authors.lastname: Watson
authors.forename: Valentine J
authors.initials: VJ
authors.lastname: Klimkowski
authors.forename: David E
authors.initials: DE
authors.lastname: Timm
authors.forename: Annick
authors.initials: A
authors.lastname: Cauvin
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Parsons
authors.forename: Qing
authors.initials: Q
authors.lastname: Shi
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Canada
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wiley
authors.forename: Gerd
authors.initials: G
authors.lastname: Ruehter
authors.forename: Britta
authors.initials: B
authors.lastname: Evers
authors.forename: Soenke
authors.initials: S
authors.lastname: Petersen
authors.forename: Larry C
authors.initials: LC
authors.lastname: Blaszczak
authors.forename: Shon R
authors.initials: SR
authors.lastname: Pulley
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Margolis
authors.forename: Graham N
authors.initials: GN
authors.lastname: Wishart
authors.forename: Beatrice
authors.initials: B
authors.lastname: Renson
authors.forename: Dirk
authors.initials: D
authors.lastname: Hankotius
authors.forename: Michael
authors.initials: M
authors.lastname: Mohr
authors.forename: Johann-Christian
authors.initials: JC
authors.lastname: Zechel
authors.forename: J
authors.initials: J
authors.lastname: Michael Kalbfleisch
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Dingess-Hammond
authors.forename: Andre
authors.initials: A
authors.lastname: Boelke
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Weichert
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004353:Drug Evaluation, Preclinical; D006860:Hydrogen Bonding; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013050:Spectrometry, Fluorescence
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4