1KAV

Human Tyrosine Phosphatase 1B Complexed with an Inhibitor

1KAV の概要

• エントリーDOI: 10.2210/pdb1kav/pdb
• 関連するPDBエントリー: 1KAK
• 分子名称: PROTEIN-TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 1, [(4-{4-[4-(DIFLUORO-PHOSPHONO-METHYL)-PHENYL]-BUTYL}-PHENYL)-DIFLUORO-METHYL]-PHOSPHONIC ACID (3 entities in total)
• 機能のキーワード: protein-inhibitor complex, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35190.85

構造登録者

Jia, Z.,Ye, Q.,Dinaut, A.N.,Wang, Q.,Waddleton, D.,Payette, P.,Ramachandran, C.,Kennedy, B.,Hum, G.,Taylor, S.D. (登録日: 2001-11-03, 公開日: 2002-06-19, 最終更新日: 2023-08-16)

主引用文献

Jia, Z.,Ye, Q.,Dinaut, A.N.,Wang, Q.,Waddleton, D.,Payette, P.,Ramachandran, C.,Kennedy, B.,Hum, G.,Taylor, S.D.
Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics.
J.Med.Chem., 44:4584-4594, 2001

PubMed Abstract: Protein tyrosine phosphatases (PTPases) are signal-transducing enzymes that dephosphorylate intracellular proteins that have phosphorylated tyrosine residues. It has been demonstrated that protein tyrosine phosphatase 1B (PTP1B) is an attractive therapeutic target because of its involvement in regulating insulin sensitivity (Elcheby et al. Science 1999, 283, 1544-1548). The identification of a second binding site in PTP1B (Puius et al., Proc. Natl. Acad. Sci. U.S.A.1997, 94, 13420-13425) suggests a new strategy for inhibitor design, where appropriate compounds may be made to simultaneously occupy both binding sites to gain much higher affinity and selectivity. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have determined the crystal structure of PTP1B complexed with two non-peptidyl inhibitors, 4 and 5, both of which contain two aryl difluoromethylenephosphonic acid groups, a nonhydrolyzable phosphate mimetic. The structures were determined and refined to 2.35 and 2.50 A resolution, respectively. Although one of the inhibitors seems to have satisfied the perceived requirement for dual binding, it did not bind both the active site and the adjacent noncatalytic binding site as expected. The second or distal phosphonate group instead extends into the solvent and makes water-mediated interactions with Arg-47. The selectivity of the more potent of these two inhibitors, as well as four other inhibitors bearing two such phosphate mimetics for PTP1B versus seven other PTPases, was examined. In general, selectivity was modest to good when compared to PTPases Cdc25a, PTPmeg-1, PTPbeta, and CD45. However, selectivity was generally poor when compared to other PTPases such as SHP-1, SHP-2, and especially TCPTP, for which almost no selectivity was found. The implications these results have concerning the utility of dual-binding inhibitors are discussed.

PubMed: 11741477
DOI: 10.1021/jm010266w

実験手法

X-RAY DIFFRACTION (2.35 Å)