X-ray Crystallography Study May Lead to New Drugs to Block Cancer Metastasis

However, the molecular mechanisms behind P-Rex1 regulation have been poorly understood.

Investigators at the University of Michigan (Ann Arbor, USA) used X-ray crystallography to determine structures of the P-Rex1 pleckstrin homology domain (a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling) bound to the headgroup of PIP3.

They reported in the April 14, 2016, online edition of the journal Structure that PIP3 binding to the pleckstrin homology domain was required for P-Rex1 activity in cells but not for membrane localization, which pointed to an allosteric activation mechanism by PIP3.

"P-Rex1 has been an attractive drug target for some time," said senior author Dr. John J.G. Tesmer, professor of pharmacology and biological chemistry at the University of Michigan. "But development of these drugs has been hindered by a lack of understanding of its structure and regulatory mechanisms. Our data have confirmed the location of the binding site, which will greatly assist with the identification or design of small molecules that target this mechanism of activation."

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