In a finding that could result in more effective angiogenesis blockers, biochemists at Yale and Cornell have discovered the three-dimensional structure of a protein linked to blood vessel growth. Researchers believe the protein, MetAP-2, enables endothelial cells in the lining of blood vessels to respond to growth factors. When the drug TNP-470 blocked the activity of the protein in tumor-bearing mice, new blood vessels failed to grow, thereby starving the tumor.
In the Nov. 13 issue of Science, Craig M. Crews, Ph.D., assistant professor of molecular, cellular, and developmental biology, and his colleagues published a “snapshot” of human MetAP-2, both alone and bound to fumagillin, the parent compound of TNP-470. “If we can get a snapshot of how one drug binds to a particular protein, we will know to what part of a protein a drug must bind,” said Crews. With such knowledge, he adds, pharmaceutical companies can more easily find drugs that might inhibit MetAP-2 by a similar mechanism. “Knowing how the drug binds to its target is an important step in tweaking the chemical structure, like carving a key to mesh with a lock, in order to make future versions of fumagillin-based drugs even more effective.”