Molecular Biology

Introduction

The Department of Molecular Biology continues to make significant progress toward understanding the fundamental molecular events that are at the core of all life. Its goal is to combine the knowledge gained in the many areas of scientific inquiry employed here -- from molecular genetics to structural biology to computational biology to name a few -- to obtain new insights into the functioning of biomolecules and their role in disease causality. Members of the department utilize the full range of contemporary research tools, including nuclear magnetic resonance spectroscopy, x-ray crystallography, electron microscopy, mass spectrometry, computer modeling, bioinformatics, and laser spectroscopy, as well as the techniques of modern molecular biology and genetics.

One of the most notable recent achievements in the department is the determination of the three-dimensional structure of the T-cell receptor, a key component of the immune response. Understanding its structure and function may enable scientists to enhance the effectiveness of the immune system through the development of new, highly targeted therapeutics. This same research team determined the structure of the erythropoietin receptor bound to a small cyclic peptide that mimics the function of the natural ligand for the receptor. In addition to providing insight into the mechanism of signal transduction by erythropoietin, this work has implications for the rational design of small-molecule drugs that stimulate the development of red blood cells. Other significant accomplishments include the structural determination of the active site of the enzyme that regulates the activity of nitric oxide, the discovery of a novel cortical neuropeptide -- cortistatin -- that induces sleep, and the solution of the structure of superoxide dismutase, a discovery that has shed light on the mechanism by which mutations cause amyotrophic lateral sclerosis, or Lou Gehrig's disease.

Protein engineering is a major activity of research activity in the department. Improved methods for the generation of catalytic antibodies have been developed, and new antibodies that efficiently catalyze disfavored chemical reactions or facilitate enantiomeric synthesis have been obtained. Directed evolution of proteins is being investigated as a means to produce novel therapeutic agents and to provide deeper understanding of the principles of molecular recognition and catalysis. Additionally, antibodies that bind cocaine have been generated and their potential use in the treatment of cocaine addiction is being explored. In the area of metalloenzyme engineering, scientists have introduced new activities into enzymes by manipulating the protein structure or by introducing new metal-binding centers. Directed evolution methods are being used to generate novel RNA and DNA enzymes.

The department continues its investigation into the theoretical and experimental understanding of protein folding. In addition, progress continues unabated in areas of molecular modeling and computational drug design. On the experimental side, novel compounds are being developed that can be designed to target specific DNA sequences and could eventually lead to a new class of therapeutic agents.

Numerous advances have been made in the elucidation of the fundamental molecular processes involved in cell cycle regulation. New insights have been obtained into the mechanism by which mitosis is regulated and the role of various cyclins and kinases in these events. Ongoing research is providing a new understanding of transcriptional regulation during cell growth and the molecular basis for DNA and RNA recognition by zinc-finger proteins. Also, the molecular neurobiology group has identified and characterized several new genes with important functions in the central nervous system, including a receptor protein implicated in mediating circadian rhythms and a new neuropeptide hormone homologous to somastostatin.