Discovery of non-covalent dipeptidyl peptidase IV inhibitors which induce a conformational change in the active site.
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.
Sheehan
Scott M
SM
Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA. SHEEHAN_SCOTT@LILLY.COM
Mest
Hans-Juergen
HJ
Watson
Brian M
BM
Klimkowski
Valentine J
VJ
Timm
David E
DE
Cauvin
Annick
A
Parsons
Stephen H
SH
Shi
Qing
Q
Canada
Emily J
EJ
Wiley
Michael R
MR
Ruehter
Gerd
G
Evers
Britta
B
Petersen
Soenke
S
Blaszczak
Larry C
LC
Pulley
Shon R
SR
Margolis
Brandon J
BJ
Wishart
Graham N
GN
Renson
Beatrice
B
Hankotius
Dirk
D
Mohr
Michael
M
Zechel
Johann-Christian
JC
Michael Kalbfleisch
J
J
Dingess-Hammond
Elizabeth A
EA
Boelke
Andre
A
Weichert
Andreas G
AG
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
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4