Structural Biology
The Department of Pharmacology at Yale University offers a unique environment to study the structure and function of important biological molecules in a highly collaborative environment. The tools of the structural biologist are essential to understand how the molecular machinery of the cell. At the Department of Pharmacology at Yale we use these tools (X-ray crystallography, NMR and Electron Microscopy) to understand how these molecular machines work, how they become dysfunctional in disease, and how to design drugs that alleviate human suffering. The use of these tools is both exciting and rewarding; the structural biologist has always been the first person to see what any protein looks like at the molecular level. These techniques drive the understanding of macromolecular function at the atomic-level.
The department has a large structural biology faculty with interests as broad as investigating the mechanisms of intramembrane proteolysis, understanding the regulation of signal transduction by tyrosine kinases and adhesion receptors, and investigating the mechanisms of chemokine signaling. These interests are directly relevant to diseases such as cancer, autoimmune disorders and Alzheimer’s. Collaborations between structural and non-structural groups are encouraged, and there are many exciting inter-disciplinary studies ongoing. The department offers a unique collaborative environment to use these tools, and a critical mass of structural biologists to provide a detailed “Structural Pharmacology” program to prospective graduate students.
Structural Biology Image Gallery
Extracellular domain structures of Receptor Tyrosine Kinases. (Front) The ternary complex structure of Fibroblast Growth Factor Receptor 1 (FGFR1) extracellular domain in complex with FGF2 and heparin. Two FGF2 molecules are colored in green, and two D2-D3 domains of FGFR1 in magenta and yellow. The heparin molecules are depicted in stick. (Back) The extracellular domain structure of KIT dimer in complex with Stem Cell Factor dimer (SCF).
SCF dimer mediates the complex formation of KIT extracellular domains. Five Ig-like domains of KIT extracellular domains are colored in blue, green, yellow, orange, and pale pink from D1 to D5, respectively. SCF dimer is colored in magenta. Image from the Schlessinger lab.
Activated Fibroblast Growth Factor Receptor 1 (FGFR1) in complex with tandem SH2 domains of Phospholipase Cγ (PLCγ). From far to near, the picture shows progression of the complex formation between FGFR1 and PLCγ. The kinase domain of FGFR1 in colored in green, N-terminal SH2 domain of PLCγ in cyan, and C-terminal SH2 domain in dark blue. An ATP and the substrate peptide are shown in stick, and a magnesium ion (Mg) in blue sphere.
The canonical phosphorylation-dependant primary binding site colored in blue is found between FGFR1 and PLCγ. In addition, the novel phosphorylation-independent secondary binding site colored in red is found in the complex structure. Image from the Schlessinger lab.