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Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24

S. Mehmood,Julien Marcoux,J. Gault,A. Quigley,S. Michaelis,S. Young,E. Carpenter,C. Robinson

Published 2016 in Nature Chemistry

ABSTRACT

Off-target binding of hydrophobic drugs can lead to unwanted side effects, either through specific or nonspecific binding to unintended membrane protein targets; however, distinguishing the binding of drugs to membrane proteins from that of detergents, lipids and cofactors is challenging. Here we use high-resolution mass spectrometry to study the effects of HIV protease inhibitors on the human zinc metalloprotease ZMPSTE24. This intramembrane protease plays a major role in converting prelamin A to mature lamin A. We monitored proteolysis of farnesylated prelamin A peptide by ZMPSTE24 and unexpectedly found retention of the C-terminal peptide product with the enzyme. We also resolved binding of zinc, lipids, and HIV protease inhibitors and showed that drug binding blocked prelamin A peptide cleavage and conferred stability to ZMPSTE24. Our results not only have relevance for the progeria-like side effects of certain HIV protease inhibitor drugs but also highlight new approaches for documenting off-target drug binding.

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