Visualizing protein dynamics and determining dynamic-activity relationships
Protein dynamics underpin protein function, from structural changes associated with signal transduction to those associated with enzyme catalysis and allosteric regulation. Determining dynamic-function relationships can open avenues to novel drug discovery pathways. Our team performs high-throughput crystallographic studies to allow for the mapping of dynamic and druggable protein sites and room-temperature and time-resolved crystallography to visualize structural transitions in operando.
Protein mechanisms and medicinal chemistry
By obtaining high-resolution structures of protein-ligand complexes, we can open avenues for further compound development and drug design. My laboratory has both a biochemistry/structural biology section as well as a synthetic chemistry section. The two areas work together to iterate quickly between compounds and protein-ligand structures.
All of our projects use synergistic approaches, employing organic chemistry and biophysics tools. We collaborate with scientists at X-ray radiation facilities (i.e., NSLSII and PETRAIII) in a bottom-up approach, harnessing the most cutting-edge synchrotron hardware available. We employ a robust crystallization approach, starting with crystallization screening at the National Crystallization Center and optimization in-house using robotics. We make use of frequent beamtime at synchrotrons to ensure rapid feedback on crystal quality and diffraction. Our approaches include the generation of large, ordered macrocrystals for both cryo- and room-temperature crystallography as well as batch microcrystallization for serial crystallography experiments.
Our current protein targets include oncogenic fusion proteins and metalloproteins, and further protein-ligand structural projects span a variety of targets through collaborative projects.
Diana Monteiro earned her Bachelor’s and Master’s degrees in Medicinal Chemistry from the University of Leeds (U.K.). She was awarded a Wellcome Trust Ph.D. Studentship with the Astbury Center for Structural Biology (School of Cellular and Molecular Biology, University of Leeds), where she pivoted her studies from chemistry to protein crystallography. As a Louise Johnson Fellow with the Center for Ultrafast Imaging at the University of Hamburg (Germany), she expanded further into methods development for room-temperature and time-resolved crystallography, working with both synchrotrons and X-ray free-electron lasers, and developing microfluidics for sample delivery to X-ray beams. In 2019, she joined the Hauptman-Woodward Medical Research Institute in Buffalo, NY, first as a postdoctoral researcher, and then progressing to an assistant investigator position. In Buffalo, she set up and oversaw the operation of an organic chemistry laboratory which worked synergistically with her structural biology research. Now as a Stadtman Investigator with the Center for Structural Biology, Dr. Monteiro's group works at the interface of structural biology and medicinal chemistry, addressing protein crystallography challenges.
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This page was last updated on Monday, October 30, 2023