Laboratory of Molecular Bioenergetics
Department of Biochemistry and Molecular Biology
The Chicago Medical School
We were not alive in the 15th century during the Renaissance - when great artists such as Donatello, da Vinci, and Michelangelo walked the earth. Nor did we experience the times of the great inventors, such as Edison and the Wright brothers. But we are very fortunate to live in the Golden Age of Molecular Biology. In a short 50 years, we have seen the structure of DNA, to the molecular structures of proteins, to the complete nucleotide sequence of the human genome. This is indeed a very exciting time for the observer, but even more so for the participant.
Teaching: My primary teaching roles for the medical school have been in the areas of DNA and RNA structure, DNA recombination and repair, gene regulation, RNA processing, modification and expression. These classes are taught in Molecular and Cellular Biology, BCS502. I also have participated in teaching Medical Biochemistry BCS505 where we discuss thermodynamics, bioenergetics, mitochondrial diseases, and mixed function oxidases. These areas are all under intense investigation in the laboratory and every effort is made to discuss the current knowledge on the topics. This sometimes means that information will be discussed that is not covered in text books. Finally, I have taught Clinical Genetics and was the course director before it was converted into the first Problem Based Learning major course in the college.
Research: The primary area of research is in the understanding of the structure, function, and regulation of the mitochondrial ATP synthase. The studies are undertaken using a variety of techniques in the area of yeast genetics, biochemistry, molecular biology, and x-ray crystallography. The x-ray diffraction data is obtained at the Advanced Photon Source in Argonne National Laboratories just outside Chicago. The x-ray crystallography is a collaborative study with Dr. John Walker at the Mitochondrial Biology Unit and Dr. Andrew Leslie at the Laboratory of Molecular Biology, both in Cambridge U.K. and part of the Medical Research Council (MRC). Outside the Walker laboratory, this is the only laboratory that is able to combine all of these techniques in the analysis of the ATP synthase.
The second area of research is in the study of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Cystic fibrosis is a common lethal disease that occurs in about 1 in every 2000 births in Caucasians. CFTR is a membrane bound protein composed of 1480 amino acids with a mass of 168,142 d and 180,000 d after glycosylation. CFTR is a member of the MRP (multidrug related protein) group, which is structurally related to the multidrug resistance family of proteins (MDR). CFTR functions as a cAMP-regulated anion channel, located on the apical plasma membrane, where it regulates secretions in the respiratory and gastrointestinal tracts. Phenotypes of patients with cystic fibrosis include pulmonary disease, pancreatic insufficiency, liver disease, high salt levels in their sweat, and infertility. Cystic fibrosis is the most frequent lethal genetic childhood disease.
Rational drug design against novel and known proteins is just one application of knowledge obtained from their high-resolution crystal structure. Frequently, the inability to obtain a large amount of the corrected folded protein precludes the ability to solve the high-resolution structure. This project tests a novel hypothesis, which if correct, will provide a rational approach for successful expression of both membrane and water soluble proteins. Human CFTR is being used as a test case to test the hypothesis but ultimately, this will hopefully lead to high resolution structural data. This project has the potential to have a very high impact on biomedical research including the treatment of cystic fibrosis.
Please visit the research page for more information on the projects and the photo gallery for images resulting from our work.
Dr. Francis Collins - NIH Director - Blogs on the FDA approval of Sirturo. Link
FDA grants approval for 1st TB drug in 40 years. Johnson&Johnson was granted approval for Sirturo, aka TMC207, for the treatment in adults with pulmonary multi-drug resistant tuberculosis. see link TMC207 binds to Fo of the ATP synthase in the corresponding oligomycin binding site of the mitochondrial ATP synthase.
10,000 downloads in 3 months of the publication!! Oligomycin frames a common drug-binding site in the ATP synthase. Proc. Natl. Acad. Sci. USA USA 28: 13961-13965, 2012. Get your's at this link.
Recognition from Argonne National Labs and GM/CA! Link
Welcome two new additions to the laboratory. Dr. Ting Xu is an accomplished crystallographer with 16 pdbs under his belt with studies on proteins from Dengue virus and M. tuberculosis. Ting obtained his Ph.D at Nanyang Technological University in Singapore and has done post-doctoral research at the NIH. We are very excited that Ting will be joining the group. Manjit Maskey obtained his B.S. at St. Cloud University in Minnesota. Manjit then got a M.S. from Iowa State University in the lab of Dr. Richard Honzatko. Manjit has completed some very studies on the binding of hexokinase to the outer mitochondrial membrane. We are excited that Manjit will be joining the lab. Welcome Ting and Manjit!
NIH Award: We are very fortunate to have received a 4 year renewal for the NIH project "Structure and Function of the ATP synthase"! Thanks to all involved. Cheers
Welcome Michal Bonar to the lab! Michal has a B.S. from U of Illinois, Urbana and an M.S. from McGill in Montreal.
Now out in PNAS - structure of the oligomycin binding site at 1.9A! LINK
Oligomycin Frames a Common Drug Binding Site in the ATP synthase (2012) J. Symersky, D. Osowski, D.E. Walters, and D.M. Mueller, PNAS, in press. Congratulations to all!
Current funding from NIGMS and NHLBI.
The structure of the yeast c10-ring was highlighted in Biopolymers - "An Open and Shut Case".
Congratulations to Henry Symersky, Vijay Pagadala, Daniel Osowski, Alexander Krah, Thomas Meier, and Jose Faraldo-Gomez - an international effort - for the NSMB paper accepted on 20-March-2012!! "Structure of the c10 ring of the yeast mitochondrial ATP synthase in the open conformation" pdb entries 3U2F, 3U32, 3U2Y, and 3UD0. These are available from the database with the structure factors to be released with the publication of the paper.
Thanks to GC/CA-CAT for their continued support and LS-CAT at the APS for their recent support.
Congratulations Vijay on your very nice paper describing the purification and properties of the yeast ATP synthase with the GFP-fusion construct. pdf
Congratulations to Kalpit on his new journey as a Ph.D. student at RFUMS!
We have entered into a collaboration with Thomas Meier and Jose Faralso-Gomez, Max Planck Institute of Biophysics, Frankfurt, Germany, to study Fo of the ATP synthase. More on this later!
Long overdue welcome to Daniel Osowski. Daniel received his B.S. from Illinois State University and currently working on the ATP synthase project.
Long overdue welcome to Kristy Shanahan into the lab in the graduate program.
Farwell to Vijay and Diana! Vijay completed his Ph.D. and is off to NIH in the research triangle in North Carolina. Diana is off to the Centre de Biochemie Structurale (CNRS) in Montpellier, France, and is engaged to be married this winter. Congratulations!
Structure of four uncoupling mutations in F1 ATPase is in JBC. This was truly a multi-person effort. Every author was critical in the completion of this project. Congratulations to all! I, and a reviewer of the manuscript, recommend the movies in the supplement - they help in the visualization of the effects of the mutations. pdf
Yamin, congratulations on completing the degree of Ph.D.! Yamin is now working at the University of Chicago as a post-doctoral fellow. (Co-incidentally, former student Hong Shen is also at the U of C.)
Yamin has published a very nice study that helps explain the structure/function relationship of the mitochondrial genome integrity mutations. See JBC.
Refinement is Complete!! The refinement of the structure of the yeast F1-ATPase in the absence of nucleotides is complete. pdf
Vijae was an Awarded American Heart Predoctoral Fellowship for 2006-2007!
Collaboration with Dr. Richard Berry in Oxford, U.K. A collaboration has been started with Dr. Berry at Oxford. Dr. Berry performs single molecule studies followed by fluorescence and atomic force microscopy. The studies are a 3 group collaborative study which include Dr. John Walker at the MRC. This is NIH funded.
Collaboration with Drs. John Walker and Andrew Leslie, Cambridge, U.K. Of course, this is old news, but we are in close collaborative studies on the yeast F1- ATPase with Drs. Walker and Leslie.
FASEB Summer Conference, Transport ATPases, June 2012.
Gordon Research Conference in Bioenergetics, 2013
Yeast Meetings, 2012 and beyond.
"Cogito cogito, ergo cogito sum"
"Best Title" Award Goes to:
Power, Sex, Suicide: Mitochondria and the Meaning of Life by Nick Lane, Oxford University Press, Oxford, U.K., ISBN 0192804812
"Genius is 1% inspiration, 99% perspiration" Thomas Edison