Structural Features that Specify Tyrosine Kinase Activity Deduced from Homology Modeling of the Epidermal Growth Factor Receptor

• Published in: Proceedings of the National Academy of Sciences - PNAS 1993-06, Vol.90 (11), p.5001-5005
• Main Authors: Knighton, Daniel R., Cadena, Deborah L., Zheng, Jianhua, Lynn F. Ten Eyck, Taylor, Susan S., Sowadski, Janusz M., Gill, Gordon N.
• Format: Article
• Language: English
• Subjects: Active sites; Adenosine Triphosphate - metabolism; Amino Acid Sequence; Amino acids; Analytical, structural and metabolic biochemistry; Binding Sites; Biochemistry; Biological and medical sciences; Calorimetry; Catalysis; Coordinate systems; Enzymes and enzyme inhibitors; ErbB Receptors - chemistry; ErbB Receptors - genetics; ErbB Receptors - metabolism; Fundamental and applied biological sciences. Psychology; Growth factor receptors; Hydrogen bonds; Models, Molecular; Models, Structural; Molecular Sequence Data; Molecules; Oxygen; Phosphates; Phosphorylation; Protein Structure, Secondary; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Protons; Sequence Homology, Amino Acid; Transferases; X-Ray Diffraction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.11.5001

To identify structural features that distinguish protein-tyrosine kinases from protein-serine kinases, a molecular model of the kinase domain of epidermal growth factor receptor was constructed by substituting its amino acid sequence for the amino acid sequence of the catalytic subunit of cAMP-dependent protein kinase in a 2.7-Å refined crystallographic model. General folding was conserved as was the configuration of invariant residues at the active site. Two sequence motifs that distinguish the two families correspond to loops that converge at the active site of the enzyme. A conserved arginine in the catalytic loop is proposed to interact with the γ phosphate of ATP. The second loop provides a binding surface that positions the tyrosine of the substrate. A positively charged surface provides additional sites for substrate recognition.