A research scientist- it is the one!
Meiling Zhang received her B.S. degree in Biotechnology from Shanghai Jiao Tong University (Shanghai, China) in 2012. After four years of research in the structure of tumor suppressor proteins by X-ray crystallography in her undergraduate, she proceeded to join Dr. Jeffrey Peng’s laboratory at the University of Notre Dame to study the conformational dynamics of a cancer/Alzheimer’s relevant protein, human Pin1, using liquid-state NMR. Her current interests focus on the interdomain allosteric mechanism and the kinetics of Pin1.
Probing “Invisible” Protein States by Solution NMR
Structure-guided drug design relies on protein structure determination, mainly protein enzymes, with an implicit emphasis on static structures. But increasing evidence shows the static view can be limiting. Enzyme activity often requires fluctuations between distinct conformations with different populations. For example, the apo states of enzymes may sample a range of conformations corresponding to different stages of its mechanism. And in inhibitor design, transiently sampled (minor) conformations can offer alternative ligand binding modes, leading to new inhibitors. As a result, it is important to complement traditional static structures with dynamic information.
Here, we illustrate NMR relaxation dispersion (RD) as a powerful approach for gaining this information. Dispersion can indirectly detect so-called “excited” conformational states – transiently-sampled conformations invisible to x-ray crystallography and conventional NMR. In ideal cases, RD can give conformational properties of the minor states and the rate constants for conformational exchange. Here we use RD to investigate the two-domain enzyme – Pin1, to determine whether its allosteric mechanism can offer new target sites for cancer therapy. Specifically, we use RD to probe the “invisible” states of a dysfunctional Pin1 variant, containing a single-site substitution outside the structural core of the WW domain. Our dispersion studies show that the mutation results in conformational exchange between the functional WT and a dysfunctional non-native conformation of the WW domain.