The Luecke Group aims to better understand the structure and function of integral membrane proteins. We also aim to identify and develop more effective drugs through research into how diseases like cancer develop and proliferate. The group will focus on two main areas of research:
Structure-function studies of integral membrane proteins
Though most genomes contain 20-30% of membrane proteins, to date we only know the atomic structures of just over 2,000 membrane proteins (vs. over 135,000 for soluble proteins). Our approach has been to employ and refine a host of specialized crystallization methods, and more recently we have begun cryo electron microscopy studies of the complex of a membrane protein with a large soluble enzyme.
Central to more than half of all human cancers is the tumor suppressor protein p53. A subset of five single-site mutations in the DNA-binding domain of p53 is found in the vast majority of these cancers (top three are ovarian, lung and colorectal). The Luecke group aims to identify compounds that restore the function of mutant p53, using structural studies.
Infection of the gastric mucosa by Helicobacter pylori affects about half the world’s population and is the primary cause of gastritis, peptic ulcer disease and gastric cancer. Gastric colonization by H. pylori depends on the expression of a proton-gated urea channel and a cytoplasmic urease unique to this pathogen. We have determined the structure of this channel which is essential for H. pylori survival in the low-pH medium of the stomach and is thus an attractive cancer target.
We have also identified compounds that inhibit the channel at submicromolar concentrations. Thus, the second general area of our research interest is structure-based drug discovery.
Structure-based drug discovery
Structural knowledge is fundamental for understanding the underlying mechanisms involved in cancer onset and proliferation. This therefore aids in the identification and the development of new and more effective drugs.
We use a multidisciplinary approach that involves crystallography, nuclear magnetic resonance, cryo electron microscopy and computational techniques to obtain structural and mechanistic insights on numerous systems.
One of our projects focuses on annexins that constitute a family of proteins that interact with phospholipid bilayers in a Ca2+-dependent manner. Mediating membrane aggregation and fusion, annexins play important roles in endo- and exocytosis, actin polymerization, inflammatory response, cancer metastasis, and the generation of plasmin. Structural studies of annexins have been essential for understanding their properties and interactions with binding partners at the atomic level. We are now characterizing several lead compounds that modulate annexin-mediated polymerization of actin, some of which have demonstrated anti-angiogenic activity.
Summary of current research focus:
- The acid-gated urea channel from Helicobacter pylori, a bacterium that is estimated to chronically infect about half of all humans, leading to ulcers and stomach cancer
- Annexin A2, metastasin (S100A4) and p11 (S100A10) are cancer and cardiovascular targets
- Reactivation of cancer mutants of p53, the well-known tumor suppressor
- Terminal uridylyl transferases involved in RNA-editing in trypanosomatids
- Inosine-5'-monophosphate dehydrogenase from the parasites P. falciparum and T. foetus
- Nuclear receptors, in particular PPAR-alpha (obesity)