Proteins: Design, Recognition, Function and CharacterizationThe investigation, control and mimicry of protein structure and function form the third theme of Yale’s Graduate Studies in Chemical Biology. Proteins occupy the central position in the machinery of the living cell by providing a diverse and robust framework for the display of a wide range of reactivities and functions. In this regard the study of protein function provides many potential points where the chemical and biological training of students intersects. Researchers at Yale have established a strong series of research programs focused on protein structure and function and also an extensive network of collaborations that expose students to concepts and techniques in Chemical Biology. Karen Anderson (Pharmacology) investigates enzymatic reactions and receptor-ligand interactions at a molecular level. Her approach is to use a combination of kinetic and structural techniques including rapid transient kinetics (stopped-flow fluorescence and rapid chemical quench methodologies), NMR, and X-Ray crystallography. This allows a quantitative and structural basis for understanding how proteins work at a molecular level. Demetrios Braddock (Pathology) is interested in the structural biology of proteins involved in human malignancy. Active projects in his lab are studies on protein:DNA complexes that regulated the c-myc oncogene, and the structure determination, mechanism of action, kinetics, and small molecule inhibition of inhibition of enzymes with stimulate angiogenesis and tumor metastasis. Enrique de la Cruz (MB&B) studies the molecular basis of free-energy coupling in non-muscle myosins using an interdisciplinary approach that combines biochemistry, biophysics and molecular biology to relate the dynamics (kinetics), energetics (thermodynamics) and conformations (structures) of biochemical intermediates in the energy transduction pathway. William Jorgensen (Chemistry) is developing and using computational methods to make quantitative predictions on the structure, energetics, and reactivity of biomolecular systems. His theoretical approach centers on computer simulations of the biomolecular systems at the atomic level with explicit inclusion of the solvent. Elias
Lolis (Pharmacology) also studies protein structure.
Using X-ray crystallography, his lab determines the three-dimensional
structure of proteins to gain a better understanding the molecular
mechanism by which they exert their biological effects. Proteins
currently under study include several cytokines such as SDF-1 Patrick Loria (Chemistry) focuses on understanding how the dynamic and structural properties of enzymes correlate with their function. This is accomplished by primarily with NMR spectroscopy but complemented by chemical biophysical techniques. Andrew Miranker (MB&B) is developing novel mass spectrometric techniques in the formation and selection of ions to address two principal areas: ionization from physiological conditions and ionization of heterogeneous samples. These approaches are being applied to the analysis of large heterogeneous systems such as cytoskeletal and amyloid fibrils and membrane bound systems such as pores and signaling complexes. Yorgo Modis (MB&B) studies how receptors of the innate immune system recognize various microbial structural motifs. The Modis lab also seeks to understand how flaviviruses use their envelope protein to enter cells. The overall goal is to guide the rational design of biologics and small molecules that modulate innate immune signaling or inhibit viral entry. Lynne Regan (MB&B) is interested in the design and characterization of proteins with novel ligand binding activities. These studies hold great promise for development in many areas, such as the development of novel bioelectrical materials and biosensors through surface immobilization. Alanna Schepartz's (Chemistry) research interests also include novel protein design . Her lab explores a general strategy that is referred to as “protein grafting” for the design of folded, miniature proteins that bind receptors (other proteins or DNA) that themselves bind a-helices. The goal is to understand how to balance the requirements of folding and recognition to generate the smallest possible molecule that retains biological activity. Michael Snyder (MCDB) and his lab members perform large scale analysis of protein biochemical activities and postranslational modifications using protein microarrays. The lab has built microarrays that contain most of the proteins of the yeast proteome. These have been screened to identify protein-protein interactions, new DNA and lipid binding activities and targets of small molecules. They have also been used to identify substrates of protein kinases and using this technology we have set up the first phosphorylation map for yeast. |
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