U-M Med-Chem Researchers Bring Membrane Protein, Peptide Data to World’s Science Community

OPM database compilers Andrei Lomize and Irina Pogozheva, with research group director, Professor Henry Mosberg.
Photography by Gregory Fox.

any drugs used to treat allergies, depression, cancer, pain, diabetes, obesity, cardiovascular disease and a variety of neurological disorders have one thing in common: they work by interacting with membrane proteins. Membrane proteins are key participants in signal transduction, transport, energy conversion, cell communication, trafficking, cell division, apoptosis, and other important cell activities.

Their critical role in cell function makes membrane proteins prized drug research targets in academic and commercial research laboratories. In fact, the world's 10 top selling drugs (as of 2006), and many more, act through membrane proteins.

The challenge comes in making sense of the thousands of membrane protein structures that are already known, with more being added all the time. To exploit the potential of membrane proteins, scientists need a shared database that characterizes protein structures in a systematic way.

Now, thanks to the work of researchers affiliated with the laboratory of Professor of Medicinal Chemistry Henry Mosberg, PhD, scientists around the world have one such source.

With their recently complied Orientations of Proteins in Membranes (OPM) database, Mosberg-group members -- Associate Research Scientist Andrei Lomize, PhD, Assistant Research Scientist Irina Pogozheva, PhD, and Research Assistant Mikhail Lomize -- have amassed comprehensive information on more than 600 membrane proteins and peptides with known three-dimensional structures.

This database is unique in that it includes a significant number of peripheral proteins that weakly associate with membranes, as well as all integral transmembrane protein complexes. In addition, the database identifies the location of the protein relative to the lipid bilayer: information that is missing in the experimental structures, but essential for the protein functioning. This missing data has been calculated using a new computational approach developed by Dr. Lomize.

This original method for optimizing the position of a protein in a fluid lipid bilayer "yields results that are consistent with experimental studies and therefore could be used to predict orientation in membranes for the majority of membrane-associated peptides and proteins with known structures," Dr. Lomize states.

All proteins in the database are organized by structural features, topology, cellular localization, organisms, and many other criteria. The authors of the database also painstakingly assembled data from hundreds of experimental studies of protein orientations in membranes.

To make this information more accessible for the scientific community --including teachers, students, and the general public -- the authors have provided an online gallery of images of all protein structures oriented with respect to the membrane.

The online site can be searched or browsed, and all files are downloadable at http://opm.phar.umich.edu.

Scientists across the world are already using OPM findings to advance their own research. In one case, the OPM database has been used to conduct a comparative analysis of numerous membrane proteins. In another, the database has been tapped to help pinpoint positioning in membranes of newly obtained crystal structures of important drug targets, such as the 2-adrenergic receptor.

OPM also has been integrated into several widely used bioinformatics resources, such as the PDBsum, OCA and MeTaDoR databases, the IMB JENA image library, as well as in the Membrane Builder server that constructs protein/membrane complexes for molecular dynamics simulations.

Beyond its utility for professional scientists, the OPM database has been adopted by academic institutions such as the University of Wisconsin and Moscow State University. Both schools are using this resource to enhance undergraduate education in biology and bioinformatics.

E-mail: him@umich.edu, almz@umich.edu, irinap@umich.edu.