Photo by Darren Baker
By tracking the evolution of Abl and Src, investigators have made discoveries that may aid the design of highly specific cancer drugs.
Abl and Src are 2 nearly identical protein kinases with a predilection to cause cancer in humans, mainly chronic myeloid leukemia and colon cancer.
The proteins are separated by 146 amino acids and one big difference: Abl is susceptible to treatment with the tyrosine kinase inhibitor imatinib (Gleevec), but Src is not.
Dorothee Kern, PhD, of Brandeis University in Waltham, Massachusetts, and her colleagues traced the journey of these 2 proteins over 1 billion years of evolution, pinpointing the exact evolutionary shifts that caused imatinib to bind well with one protein and poorly with the other.
This new approach to researching enzymes and their binding sites may have a major impact on the development of cancer drugs, the investigators said.
They published their findings in Science.
To determine why imatinib binds with Abl but not Src, Dr Kern and her colleagues turned back the evolutionary clock 1 billion years.
This revealed Abl and Src’s common ancestor, a primitive protein in yeast the team dubbed “ANC-AS.” They mapped out the family tree, searching for changes in amino acids and molecular mechanisms.
“Src and Abl differ by 146 amino acids, and we were looking for the handful that dictate Gleevec specificity,” Dr Kern said. “It was like finding a needle in a haystack and could only be done by our evolutionary approach.”
As ANC-AS evolved in more complex organisms, it began to specialize and branch into proteins with different regulation, roles, and catalysis processes—creating Abl and Src.
By following this progression, while testing the proteins’ affinity to imatinib along the way, the investigators were able to whittle down the 146 different amino acids to 15 that are responsible for imatinib specificity.
These 15 amino acids play a role in Abl’s conformational equilibrium—a process in which the protein transitions between 2 structures. The main difference between Abl and Src, when it comes to binding with imatinib, is the relative times the proteins spend in each configuration, resulting in a major difference in their binding energies.
By understanding how and why imatinib works on Abl—and doesn’t work on Src—scientists have a jumping off point to design other drugs with a high affinity and specificity, and a strong binding on cancerous proteins.
“Understanding the molecular basis for Gleevec specificity has opened the door wider to designing good drugs,” Dr Kern said. “Our results pave the way for a different approach to rational drug design.”
