Better Binding Through Chemistry

immune system during a biological assault, and postdoctoral fellow Roger Briesewitz got the idea for their approach while studying mutant bacteria that showed enhanced affinity of rapamycin for its target, tor, a protein involved in cell cycle regulation. Certain microbes block the proliferation of competing microbes by secreting rapamycin. The "drug" rapamycin achieves inhibition in two steps: First, it binds to a presenting protein, FKBP (for FK506-binding protein), and then the drug-protein complex binds to the tor protein.

Remarkably, Crabtree says, all of the mutations that improved protein affinity were at the interface between the two proteins. No mutations were found in regions of either protein that directly bound to rapamycin. In thinking more about this unexpected result, Crabtree and his colleagues realized that their observation was related to the molecular mechanism by which small peptides, called antigens, turn on T cells. Antigens first bind to a much larger protein known as the major histocompatibility complex (MHC). X-ray crystallography studies have shown that both members of an antigen-MHC duo interact with the T-cell receptor.

"In fact, the antigen by itself has no affinity for the T-cell receptor, but when it's held by MHC, it has a very, very high affinity interaction," said Crabtree. "So, it's the presenting molecule that gives the high affinity.

"Similarly, the immune-suppressing drugs cyclosporin and FK506 have no special affinity for calcineurin--their target protein in the human cell--until they bind to large presenting proteins. In fact, when one mixes cyclosporin and calcineurin in vitro, there's no detectable binding. But when you have cyclosporin presented by a protein called cyclophilin, there is perhaps a million-fold increase in binding affinity to its target."

In a study published in the March 2, 1999, issue of the Proceedings of the National Academy of Sciences, the

Contact: Jim Keeley
Howard Hughes Medical Institute

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