We are working to decipher the mechanism and function of integral membrane proteins involved in human disease and the means by which drug molecules and antibodies activate and inhibit function. Specifically, small molecular chaperones are known to improve the folding of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), alleviating symptoms and increasing life expectancy of CF patients. Small drug molecules also show great promise in reversing cancer multi-drug resistance through several drug transporters in the body. Most efficacious pharmaceutical agents must be identified through time-consuming and expensive high-throughput drug screens and functional assays. Even though approximately one-third of current drugs target membrane proteins, a structure-based drug design strategy is precluded until three-dimensional crystal structures of relevant mammalian membrane proteins become available. We aim to overcome this hurdle by solving high-resolution x-ray crystal structures of these important human membrane proteins in complexes with molecular chaperones, pharmaceutical molecules and other protein partners. The structures will enable a bona fide analysis of drug-protein interactions and provide three-dimensional scaffolds for in silico drug screening and next-generation drug design.

Our laboratory is ideally located in the department of Pharmacology at UAB and the Center for Biophysical Structural Engineering, which allows us to interact and collaborate with experts in both medicine and basic research located in the medical school clinic and surrounding biochemistry laboratories. The PI is also a member of the Comprehensive Cancer Center at UAB which allows us to work closely with experienced clinicians and scientists to take our research results to animal studies and clinical trials.

Radka, CD, DeLucas, LJ, Lawrenz, MB, Perry, RD, & Aller SG. Crystal structure of Yersinia pestis virulence factor YfeA reveals two polyspecific metal-binding sites. Acta Crystallographica Section D., Apr (2017), in press.

Ehrhardt A., Chung WJ, Pyle LC, Wang W, Nowotarski K, Mulvihill CM, Ramjeesingh M, Hong J, Velu SE, Lewis HA, Atwell S, Aller SG, Bear CE, Lukacs GL, Kirk KL, & Sorscher EJ. Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop. J. Biol Chem., Jan (2016).

Pan, L. & Aller, S.G. Equilibrated Atomic Models of Outward-Facing P-glycoprotein and Effect of ATP Binding on Structural Dynamics. Scientific Reports 5, 7880: Jan (2015).

Li, Jingzhi, Jaimes F. Kimberly & Aller, S.G. Refined Structures of Mouse P-glycoprotein. Protein Science 23, 34-46, Nov. (2014).

Skamel, C., Aller, S.G. & Waffo, A. RNA Coliphage QBeta Display for in Vitro Evolution and Affinity Maturation. PLoS ONE, Dec, (2014).

Aller, S.G., Yu, J., Ward, A.B., Chittaboina, S., Zhang, Q., Trinh, Y., Harrell, P., Urbatsch, I.L., & Chang, G. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323, 1718-1722 (2009).

De Feo, C.J., Aller, S.G., Siluvai, G.S., Blackburn, N.J. & Unger, V.M. Three-Dimensional structure of the human copper transporter hCTR1. Proceedings of the National Academy of Sciences of the United States of America 106, 4237-42 (2009).

Aller, S.G. & Unger, V.M. Projection structure of the human copper transporter CTR1 at 6 Å resolution reveals a compact trimer with a novel channel-like architecture. Proceedings of the National Academy of Sciences of the United States of America 103, 3627-32 (2006).

Aller, S.G., Eng, E.T., De Feo, C.J. & Unger, V.M. Eukaryotic CTR copper uptake transporters require two faces of the third transmembrane domain for helix packing, oligomerization, and function. Journal of Biological Chemistry 279, 53435-41 (2004).

Aller, S.G., Lombardo, I.D., Bhanot, S. & Forrest, J.N., Jr. Cloning, characterization, and functional expression of a CNP receptor regulating CFTR in the shark rectal gland. American Journal of Physiology 276, C442-9 (1999).