Modeling Studies of the Interactions between the Insulin Receptor Kinase Domain and Protein Tyrosine Phosphatase 1B

1999 ◽  
Vol 121 (15) ◽  
pp. 3579-3589 ◽  
Author(s):  
Nicholas R. Glover ◽  
Alan S. Tracey
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Kinase Domain ◽  
Protein Tyrosine Phosphatase 1B ◽  
Receptor Kinase ◽  
Protein Tyrosine ◽  
Modeling Studies ◽  
Insulin Receptor Kinase

Comparative modeling of the phosphatase and kinase domains of protein tyrosine phosphatase and insulin receptor kinase from Drosophila melanogaster (DPTP61fm), and a computational study of their mutual interactions

2002 ◽  
Vol 80 (2) ◽  
pp. 225-239 ◽  
Author(s):  
Sanchita Hati ◽  
Sudeep Bhattacharyya ◽  
James V Price ◽  
Alan S Tracey
Keyword(s):  
Hydrogen Bonding ◽  
Drosophila Melanogaster ◽  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Computational Study ◽  
Tyrosine Phosphatase ◽  
Receptor Kinase ◽  
Protein Tyrosine ◽  
Insulin Receptor Kinase ◽  
High Degree

The components and functions of the insulin receptor kinase signaling pathway have been conserved in a broad range of Metazoa ranging from mammals to insects and nematodes. There is a high degree of sequence homology and functional similarity between the human insulin receptor kinase (IRK) and the drosophila (Drosophila melanogaster) form (DIRK) of this enzyme. Similarly, a high degree of homology exists between human protein tyrosine phosphatase 1B (PTP1B) (which directly regulates IRK) and its drosophila counterpart DPTP61F (DPTP). However, genetic and biochemical studies have yet to demonstrate that DPTP61F acts in the DIRK pathway. Comparative structural modeling techniques using the known structures of human IRK and PTP1B as templates have yielded structures for the drosophila enzymes. The derived structures confirm that there is a high level of structural conservation at the tertiary level. Association of the DIRK and DPTP enzymes with each other was then investigated with a view to ascertaining whether DIRK might be a substrate of the DPTP. Evaluation of the interaction surfaces, including hydrophobic patch, shape, hydrogen bonding, and electrostatic compatibility, strongly suggested that the drosophila insulin receptor is a substrate of the DPTP. The interaction surfaces of the human and drosophila enzymes are structurally similar, although changes in critical residues modify possible electrostatic and hydrogen-bonding interactions. This suggests that in the mixed systems, DPTP–IRK or PTP1B–DIRK, the kinase domain will be a comparatively poor substrate for phosphatase activity when compared with the native systems.Key words: protein tyrosine phosphatase, insulin receptor kinase, Drosophila melanogaster, comparative protein modeling, surface topology, interaction zone.

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