Structural Biology

Macromolecules underlie all biological processes and play either dynamic roles in catalysis or signaling or static roles in scaffolding or information storage. Knowing the structure of the proteins and nucleic acids involved in a particular biological process is key to understanding their biochemical function as well as their specificity and mechanism of action.

Research conducted by the investigators in the Structural Biology program is aimed at elucidating the structural basis for a variety of important biological processes, including signal transduction, membrane transport, microbial pathogenesis, neural development, intercellular interactions, and the regulation of gene expression. Among the methods being used to examine macromolecular structure are x-ray crystallography, electron microscopy, mass spectrometry, biochemical and genetic analysis, and computer-assisted structural modeling. In addition, high resolution ultrasound and magnetic resonance imaging methods are being developed to visualize mammalian organs in utero and after birth.

Administrative Assistants: Constance Kontos, Samantha Peruyero

Belasco Lab

Post-transcriptional processes play a crucial role in controlling gene expression in all organisms. Our research is aimed at elucidating post-transcriptional gene regulation in eukaryotic and bacterial cells. We are particularly interested in the proteins, RNA elements, and molecular mechanisms that govern mRNA degradation, a key regulatory process that directly impacts gene expression through its influence on mRNA abundance. We are also investigating the mechanisms by which microRNAs regulate gene expression in mammalian cells via changes in mRNA translation and stability. Finally, we have developed a set of broadly applicable genetic methods for rapidly cloning and characterizing proteins important for post-transcriptional gene regulation, and we are using these and other methods to examine how such proteins (e. g., HIV-1 Rev) assemble on their RNA targets and control gene expression.

Hubbard Lab

My laboratory is interested in the molecular mechanisms by which the insulin receptor and other receptor tyrosine kinases (RTKs) are activated upon ligand binding, and the structural basis for recruitment of downstream signaling proteins to activated receptors. The main experimental technique we employ for three-dimensional structure determination is x-ray crystallography. Members of the RTK family include, among others, the insulin and insulin-like growth factor-1 (IGF1) receptors, fibroblast growth factor receptor, platelet-derived growth factor receptor, and epidermal growth factor receptor. RTKs play critical roles in signal transduction pathways that mediate cell proliferation, differentiation, migration and metabolism, both in organismal development and in adult homeostasis. RTKs have also been implicated in the onset or progression of numerous cancers.

Xu Lab

We study the molecular mechanism by which genetic information is inherited and expressed in eukaryotes. We use X-ray crystallography as our main tool to study the structure and function of key players in chromosomal replication, transcriptional regulation, and mRNA processing. We are interested in understanding the structural basis of origin recognition and pre-replicative complex assembly in DNA replication; post-translation modification of histones, the assembly, inheritance,and dynamics of higher order chromatin structures in transcriptional regulation; and protein-protein and protein RNA interactions in splice site selection and splicing-coupled nuclear export and decay of messenger RNA. Eukaryotic DNA replication and gene expression are highly regulated processes. For example, chromosomes are replicated once and only once per cell cycle, and transcriptional activation or repression critically depends on the post-transcriptional modification status of the chromatin domain in which the genes are located. In addition, alternative splicing can produce many different messengers from a single transcript, which drastically increases the complexity of the proteome and is important for many processes such as development and differentiation. Deregulated DNA replication or gene expression can lead to catastrophic consequences such as cancer. The structural information that results from our studies should facilitate mechanistic understandings of these fundamental biological processes as well as aid the development of therapeutic agents against human pathologies and diseases such as cancer.

Neubert Lab

The main focus of our lab is the study of proteins and their roles in cellular signaling events. While great strides in understanding intracellular signal transduction have been made in recent years by using molecular biological techniques, we feel that a more complete understanding of the dynamics of intracellular decision-making processes can be gained only by studying the proteins directly. We use mass spectrometry as the main tool for our studies because of the wide variety of information about protein structure it can provide while requiring only small amounts of protein for analysis.

Stokes Lab

Our lab focuses on membrane transport by ATP-dependent ion pumps and intercellular adhesion by cell-cell junctions. We use electron microscopy to determine 3D structures of proteins involed in these processes. For membrane transport, we use electron crystallography to study helical assemblies of Ca-ATPase and its relatives in the family of P-type ATPases. For intercellular adhesion, we use electron tomography to map the molecular architecture of desmosomes and adherens junctions in situ.

Turnbull Lab

Extensive genetic information and new techniques to manipulate the genome of the mouse have led to its widespread use for studying development and modeling human diseases. In this rapid proliferation of methods to genetically engineer mice, in vivo technologies to analyze anatomical structure and function in the mouse have not kept pace. The results of transgenic and gene targeting experiments are usually analyzed using histological methods, which are static and two-dimensional, making it difficult to understand the underlying developmental and disease processes, which are dynamic and three-dimensional. We are developing both ultrasound and magnetic resonance micro-imaging approaches to provide noninvasive, dynamic structural and functional data on developmental and disease processes in mice.

Wang Lab

Our group aims to understand the molecular mechanisms of secondary membrane transporter proteins using X-ray crystallography and cryo-electron microscopy. Secondary active transporters use a solute gradient to drive the translocation of ions, sugars, drugs, nucleosides, amino acids, or neurotransmitters, across the membrane. Many of such proteins are involved in the pathogenesis of diseases, and some are also drug targets. For example, both Prozac and cocaine exercise their effects by binding to secondary membrane transporters. Crystal structures of such proteins will directly reveal the substrate-binding site and the substrate-translocation pathway, and can suggest the conformational changes required for the substrate translocation.