Crystal Structures of Human Dipeptidyl Peptidase IV in its Apo and Diprotin B-complexed Forms
Hajime HIRAMATSU, Kiyoshi KYONO, Atsushi YAMAMOTO, Kazuhiko SAEKI, Hideaki SHIMA, Shigeru SUGIYAMA,
Koji INAKA, Ryo SHIMIZU,
Shigeru SUGIYAMA
Maruwa Food Industries Inc., Nara 639-1123, Japan
Mol Logics Inc., Kyoto 619-0237, Japan
Search for more papers by this authorCorresponding Author
Ryo SHIMIZU
Tanabe Seiyaku Co. Ltd, Osaka 532-8505, Japan
*Corresponding author: Tel, 81-6-63002568; Fax, 81-6-63002528; E-mail, [email protected]Search for more papers by this authorHajime HIRAMATSU, Kiyoshi KYONO, Atsushi YAMAMOTO, Kazuhiko SAEKI, Hideaki SHIMA, Shigeru SUGIYAMA,
Koji INAKA, Ryo SHIMIZU,
Shigeru SUGIYAMA
Maruwa Food Industries Inc., Nara 639-1123, Japan
Mol Logics Inc., Kyoto 619-0237, Japan
Search for more papers by this authorCorresponding Author
Ryo SHIMIZU
Tanabe Seiyaku Co. Ltd, Osaka 532-8505, Japan
*Corresponding author: Tel, 81-6-63002568; Fax, 81-6-63002528; E-mail, [email protected]Search for more papers by this authorAbstract
Dipeptidyl peptidase IV (DPPIV), which belongs to the prolyloligopeptidase family of serine proteases, is known to have a variety of regulatory biological functions and has been shown to be implicated in type 2 diabetes. It is therefore important to develop selective human DPPIV (hDPPIV) inhibitors. In this study, we determined the crystal structure of apo hDPPIV at 1.9 Å resolution. Our high-resolution crystal structure of apo hDPPIV revealed the presence of sodium ion and glycerol molecules at the active site. In order to elucidate the hDPPIV binding mode and substrate specificity, we determined the crystal structure of hDPPIV-diprotin B (Val-Pro-Leu) complex at 2.1 Å resolution, and clarified the difference in binding mode between diprotin B and diprotin A (Ile-Pro-Ile) into the active site of hDPPIV. Comparison between our crystal structures and the reported apo hDPPIV structures revealed that positively charged functional groups and conserved water molecules contributed to the interaction of ligands with hDPPIV. These results are useful for the design of potent hDPPIV inhibitors.
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