Drug Resistance

Protein kinases are a group of enzymes that transfer a phosphate from a molecule, such as the cofactor ATP, to one or more amino acid residues in a signaling protein. Over-functioning results in uncontrollable growth of cells, a tumor formation. ATP binds in the ATP-binding site of the tyrosine kinase domain and makes 2 important hydrogen bonds to the protein. A threonine side-chain at position 790 is present in the binding interaction. The binding of ATP to the tyrosine kinase domain of the protein leads to phosphorylation of the tyrosine residue, and as a result, proliferation of cells. The drug Iressa or Gefitinib is a Tyrosine Kinase inhibitor that blocks the binding of ATP, and thus no phosphorylation. Although it is similar in size, Iressa does not resemble the structure of the ATP molecule, but the drug binds in the ATP-binding pocket and prevents the protein from phosphorylation.
The higher concentration of Iressa as compared to ATP allows the drug to prevent ATP from binding. The crucial binding region for Iressa is at the side chain of the amino acid Threonine at position 790. This binding prevents the endogenous ATP molecule from binding to the tyrosine kinase domain.
The protein has shown that it can become resistant to Iressa by mutation of an amino acid. Threonine, at position 790 where Iressa binds is mutated to Methionine.. Because the water molecule is no longer close to Iressa after the amino acid mutation, the interaction between Iressa and the protein is weakened and no hydrogen bonding can occur. The low binding affinity for Iressa allows the ATP molecule to enter the ATP-binding site and bind to the protein, leading to more phosphorylation of the tyrosine residue, and as a result, proliferation of cells and tumor growth once again.

Credit:

Sean Gilman
Stephen Norris

Dr. Bongsup Cho
Prof Roy Bergstrom