Structural Biology

What is Structural Biology? 

Structural biology refers to the three-dimensional arrangement of biological macromolecules including the arrangement of atoms within a protein or nucleic acid, the arrangement of proteins and nucleic acids into complex structures and the arrangement of such complexes in a cell. Structure is essential for understanding basic biological function and can also be applied directly towards the development of therapeutics using three-dimensional structures of proteins for which inhibition would be beneficial.   

The past few decades have seen a revolution structural biology. Macromolecular crystallography has become a mature technique that permits structures to be obtained rapidly after suitable crystals have been grown, results that can be complemented by small angle solution X-ray scattering. NMR has emerged as a particularly useful technique to examine macromolecular dynamics in solution. Recently, cryo electron microscopy (cryoEM) has exploded with the advent of direct detectors that permit near atomic resolution on macromolecular complexes. We at UMass are well poised to harness all of these technical advances and apply them to important biological questions.

Our research in the area of Structural Biology

The Biochemistry and Molecular Pharmacology (BMP) department embraces experimental and computational approaches to determine the structure and dynamics of macromolecules that are involved in many biologically important systems. Structural biological research at UMass Medical School is diverse including basic issues of biological function often with an emphasis on clinically important problems. Among the areas actively being investigated are the processing of genetic material by molecular machines (Kelch); molecular recognition and specificity of RNA-binding proteins involved in mRNA stability in cancer-related proteins (Massi); molecular architecture involved in membrane targeting (Munson); understanding the molecular basis of luciferase function (Miller). 

Some of our research includes using the three dimensional structures of key proteins to design inhibitory compounds that could become therapeutically useful. Such research includes: structural basis for drug resistance and specificity for critical viral and innate immune proteins (Schiffer); design of inhibitors targeting a central player in cancer (Royer); developing therapeutics targeting arginine modifying enzyme, including the Protein Arginine Deiminases, which have been shown to play roles in a variety of inflammatory diseases and cancer (Thompson). Additionally, Dr. Chen Xu, our director of the new cryoEM facility is actively developing cryoEM protocols that will permit UMMS to become a leader in structural analysis of protein complexes. 

Our breakthrough discoveries 

Among our important discoveries are the use of hundreds co-crystal structures of HIV and HCV proteases with substrates and inhibitors to develop the substrate envelope theory of drug resistance (Schiffer); gaining an atomic-level understanding of how the clamp loader ATPase opens the clamp to load it onto DNA (recognized as one of the top 54 structures in the history of crystallography) (Kelch); elucidating the molecular origin and functional effects of structural order and disorder in RNA-binding proteins (Massi); structure-based design of inhibitors for Protein Arginine Deiminases and elucidating the ordered calcium binding in PAD2 (Thompson); discovery of latent luciferase activity in nonluminescent organisms (Miller); development of computational algorithms for predicting protein-protein complex structures (Weng). We anticipate that the breakthrough discoveries are likely to continue at a strong pace especially given the new cryoEM facility being established under the leadership of Dr. Chen Xu. 

Our PIs that are conducting research in the area of Structural Biology

C. Robert Matthews

Osman Bilsel

Dan Bolon

Anthony Carruthers

Job Dekker

Brian Kelch

Francesca Massi

Stephen Miller

Mary Munson

William Royer

Celia Schiffer

Paul Thompson

Zhiping Weng

Chen Xu

Jill Zitzewitz

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