Understanding the Impact of the P-loop Conformation on Kinase Selectivity

• Published in: Journal of chemical information and modeling Vol. 51; no. 6; pp. 1199 - 1204
• Main Authors: Guimarães, Cristiano R. W, Rai, Brajesh K, Munchhof, Michael J, Liu, Shenping, Wang, Jian, Bhattacharya, Samit K, Buckbinder, Leonard
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 27-06-2011
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Crystal structure; Databases, Protein; Enzymes and enzyme inhibitors; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - chemistry; Extracellular Signal-Regulated MAP Kinases - metabolism; Fundamental and applied biological sciences. Psychology; Kinases; Models, Molecular; Protein Conformation; Protein Folding; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Statistical analysis; Substrate Specificity; Transferases; Statistical analysis; Enzyme; Residue; Transferases; Database; Selectivity; Structural analysis; Conformation; Crystalline structure
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci200153c

This work addresses the link between selectivity and an unusual, folded conformation for the P-loop observed initially for MAP4K4 and subsequently for other kinases. Statistical and computational analyses of our crystal structure database demonstrate that inhibitors that induce the P-loop folded conformation tend to be more selective, especially if they take advantage of this specific conformation by interacting more favorably with a conserved Tyr or Phe residue from the P-loop.