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.

David M. Mueller. Ph.D.

Teaching: My primary teaching roles for the medical school are 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 participate 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.

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 Dunn Human Nutrition 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.