Crystal structure of the bacterial membrane protein LeuT (green), showing two sodium ions (red) and the amino acid leucine in a central cavity. (courtesy of Derek Claxton/Mchaourab lab)
‘Glue grant’ to enhance study of membrane proteins
The National Institute of General Medical Sciences has awarded a 5-year, $22.5 million “glue grant” to an international team of scientists who will investigate how the structure and movement (structural dynamics) of membrane proteins determine their functions, which range from generating cellular energy to helping hold cells in a tissue together.
The funding establishes the Membrane Protein Structural Dynamics Consortium, comprising investigators from 14 institutions in four countries, including a team at Vanderbilt University Medical Center led by Hassane Mchaourab, Ph.D., professor of Molecular Physiology & Biophysics, Physics and Chemistry.
“This is a tremendous opportunity to combine the expertise of experimentalists and theoreticians to take on the 'grand challenge' of defining the mechanisms through which conformational dynamics impart function to key membrane protein classes,” said Mchaourab.
In addition to providing new insights about normal cell function, the research supported by this grant could help scientists better understand a wide range of diseases caused by faulty membrane proteins, such as heart disease, diabetes and some neurological disorders. And, because more than half of today's medicines target membrane proteins, the findings could pave the way for new or improved drugs.
Mchaourab's team has two projects within the consortium. The goal, he said, is to “establish the energy landscape that governs the dynamics and function” of two protein “archetypes,” or representatives, of two important classes of membrane proteins.
The first project focuses on the dynamics of P-glycoprotein, a type of multi-drug transporter implicated in the resistance of cancer cells to chemotherapy. This protein acts as an “efflux pump,” ejecting drugs from the cell and rendering them ineffective. Identifying how these transporters work might reveal strategies to combat or prevent the development of drug resistance in cancer as well as resistance to antibiotics.
The second project focuses on LeuT, a bacterial protein that represents a family of transporters, the neurotransmitter: sodium symporter (NSS).
These proteins transport neurotransmitters like serotonin, norepinephrine and dopamine (chemicals involved in mood regulation and addiction) into cells, clearing them from the extracellular space and stopping neurotransmission.
Mchaourab's group hopes to determine the structural dynamics of LeuT that allow it to transport the amino acid leucine into and out of bacterial cells. Because neurotransmitter transporters are primary targets for psychostimulant drugs (for example, cocaine and amphetamine) and for some antidepressants, understanding how they work could suggest new methods for treating addiction and mood disorders.
Eduardo Perozo, Ph.D., at the University of Chicago, is leading the consortium, which also involves scientists at Cornell University, Columbia University, Johann Wolfgang Goethe-Universität (Germany), the National Institutes of Health, Stanford University, the University of California-Los Angeles, the University of Illinois, the University of Pittsburgh, the University of Toronto (Canada), the University of Virginia, the University of Wisconsin, and Utrecht University (the Netherlands).