Biomolecular Structure and Interactions
Function, Mechanisms, Design and Recognition
The research in this focus area is involved with the structures of biological macromolecules and their complexes as well as the interactions of molecules in cells that control all regulation from replication to metabolism. During the last five year period the Department has established a Georgia Research Alliance-NIH-NSF funded biomolecular interaction core facility.
The core facility also has biosensor-surface plasmon resonance instruments for real time detection of binding affinities and kinetics and well as microcalorimeters for analysis of biomolecular interactions. A small sampling of the projects in this area, all of which have received external funding in the last five years, will give an overview of the research. Ca2+ is an essential structural component and helps regulate cellular processes.
In order to understand these critically important biological processes, Dr. Jenny Yang has developed novel approaches for creating a single Ca2+binding site in order to dissect the key structural factors that control Ca2+ binding affinity, conformational change and cooperativity. The key determinants for Ca2+ affinity can be systematically introduced into a stable host protein frame and evaluated by eliminating or minimizing the contribution of conformational change.
Dr. Irene Weber is conducting research in AIDS and cancer. Her group carries out both crystallographic and biochemical analysis and interaction studies on proteins implicated in disease. The Tcl1 oncoprotein and HIV protease have been recently investigated. The interaction of HIV protease with novel inhibitors is being studies by both structural; and interaction methods. The long range objective of these studies is to develop new therapeutic agents to treat AIDS and cancer.
The biomolecular interactions group also has a very strong base of research in the nucleic acid area. Dr. David Wilson, in collaboration with the drug design and synthesis team of Dr. David Boykin, is investigating the interaction of antiparasitic drugs with specific target sites in the parasite mitochondrial DNA.
The information from the interaction as well as QSAR and structural studies is used by the Boykin group in the design of new compounds which have a high potential of improved activity. This effort has already resulted in a clinical candidate which has passed both Phase I and II clinical trials with excellent results. The research of this group has also resulted in a number of fundamental advances in the understanding of nucleic acid molecular recognition.
Dr. Markus Germann focuses on RNA-protein regulatory elements that are important in disease. They are investigating the interaction of novel zinc finger proteins with the HIV-1 RNA. They use a broad range of methods, but particularly NMR, to understand how engineered zinc finger proteins bind their RNA substrates. In order to improve the substrate-affinity they use NMR structural data for site directed mutagenesis experiments and structure guided phage display selection. Drs. Germann and Wilson are collaborating on structural studies to better understand the molecular basis of DNA minor groove recognition.
Dr. Kathy Grant is carrying out a project on the design, syntheses, and characterization of photoactive DNA intercalators that can act as DNA structural probes and have the development potential to be effective anti-tumor agents. Several of the designed compounds photocleave DNA with high efficiency under near physiological conditions of temperature and pH. Beth Wilson from the Grant laboratory has worked in Prof. Lorente’s laboratory in Spain as a Visiting Scholar and she succeeded in synthesizing a unique series of phenothiazine-based intercalators. Because phenothiazines are activated by wavelengths of light transparent to most biological membranes, they possess a significant, major advantage over most other chromophores for applications in photodynamic cancer therapy.
Dr. Zhen Huang uses Se modification of nucleic acids in structural studies. Dr. Huang’s laboratory is carrying out both the synthetic and x-ray crystallography parts of the project.