2FJM

The structure of phosphotyrosine phosphatase 1B in complex with compound 2

Summary for 2FJM

• Entry DOI: 10.2210/pdb2fjm/pdb
• Related: 2fjn
• Descriptor: Tyrosine-protein phosphatase, non-receptor type 1, CHLORIDE ION, (4-{(2S,4E)-2-(1H-1,2,3-BENZOTRIAZOL-1-YL)-2-[4-(METHOXYCARBONYL)PHENYL]-5-PHENYLPENT-4-ENYL}PHENYL)(DIFLUORO)METHYLPHOSPHONIC ACID, ... (5 entities in total)
• Functional Keywords: phosphatase, secondary binding site, selectivity, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 73750.60

Authors

Asante-Appiah, E.,Patel, S.,Desponts, C.,Taylor, J.M.,Lau, C.,Dufresne, C.,Therien, M.,Friesen, R.,Becker, J.W.,Leblanc, Y.,Scapin, G. (deposition date: 2006-01-03, release date: 2006-01-17, Last modification date: 2023-08-30)

Primary citation

Asante-Appiah, E.,Patel, S.,Desponts, C.,Taylor, J.M.,Lau, C.,Dufresne, C.,Therien, M.,Friesen, R.,Becker, J.W.,Leblanc, Y.,Kennedy, B.P.,Scapin, G.
Conformation-assisted inhibition of protein-tyrosine phosphatase-1B elicits inhibitor selectivity over T-cell protein-tyrosine phosphatase.
J.Biol.Chem., 281:8010-8015, 2006

PubMed Abstract: PTP-1B represents an attractive target for the treatment of type 2 diabetes and obesity. Given the role that protein phosphatases play in the regulation of many biologically relevant processes, inhibitors against PTP-1B must be not only potent, but also selective. It has been extremely difficult to synthesize inhibitors that are selective over the highly homologous TCPTP. We have successfully exploited the conservative Leu119 to Val substitution between the two enzymes to synthesize a PTP-1B inhibitor that is an order of magnitude more selective over TCPTP. Structural analyses of PTP-1B/inhibitor complexes show a conformation-assisted inhibition mechanism as the basis for selectivity. Such an inhibitory mechanism may be applicable to other homologous enzymes.

PubMed: 16407290
DOI: 10.1074/jbc.M511827200

Experimental method

X-RAY DIFFRACTION (2.1 Å)