1Q6T

THE STRUCTURE OF PHOSPHOTYROSINE PHOSPHATASE 1B IN COMPLEX WITH COMPOUND 11

Summary for 1Q6T

• Entry DOI: 10.2210/pdb1q6t/pdb
• Related: 1Q6J 1Q6M 1Q6N 1Q6P 1Q6S
• Descriptor: Protein-tyrosine phosphatase, non-receptor type 1, MAGNESIUM ION, 6-[4-((2S)-2-(1H-1,2,3-BENZOTRIAZOL-1-YL)-3-{4-[DIFLUORO(PHOSPHONO)METHYL]PHENYL}-2-PHENYLPROPYL)PHENYL]-2-[(1S)-1-METHOXY-3-METHYLBUTYL]QUINOLIN-8-YLPHOSPHONIC ACID, ... (4 entities in total)
• Functional Keywords: phosphatase, secondary binding site, selectivity, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side : P18031
• Total number of polymer chains: 2
• Total formula weight: 74178.48

Authors

Scapin, G.,Patel, S.B.,Becker, J.W.,Wang, Q.,Desponts, C.,Waddleton, D.,Skorey, K.,Cromlish, W.,Bayly, C.,Therien, M.,Gauthier, J.Y.,Li, C.S.,Lau, C.K.,Ramachandran, C.,Kennedy, B.P.,Asante-Appiah, E. (deposition date: 2003-08-13, release date: 2003-09-30, Last modification date: 2023-08-16)

Primary citation

Scapin, G.,Patel, S.B.,Becker, J.W.,Wang, Q.,Desponts, C.,Waddleton, D.,Skorey, K.,Cromlish, W.,Bayly, C.,Therien, M.,Gauthier, J.Y.,Li, C.S.,Lau, C.K.,Ramachandran, C.,Kennedy, B.P.,Asante-Appiah, E.
The Structural Basis for the Selectivity of Benzotriazole Inhibitors of Ptp1B
Biochemistry, 42:11451-11459, 2003

PubMed Abstract: Protein tyrosine phosphatase 1B (PTP1B) has been implicated in the regulation of the insulin signaling pathway and represents an attractive target for the design of inhibitors in the treatment of type 2 diabetes and obesity. Inspection of the structure of PTP1B indicates that potent PTP1B inhibitors may be obtained by targeting a secondary aryl phosphate-binding site as well as the catalytic site. We report here the crystal structures of PTP1B in complex with first and second generation aryldifluoromethyl-phosphonic acid inhibitors. While all compounds bind in a previously unexploited binding pocket near the primary binding site, the second generation compounds also reach into the secondary binding site, and exhibit moderate selectivity for PTP1B over the closely related T-cell phosphatase. The molecular basis for the selectivity has been confirmed by single point mutation at position 52, where the two phosphatases differ by a phenylalanine-to-tyrosine switch. These compounds present a novel platform for the development of potent and selective PTP1B inhibitors.

PubMed: 14516196
DOI: 10.1021/bi035098j

Experimental method

X-RAY DIFFRACTION (2.3 Å)