The human body contains a million or so distinct proteins. Chemistry harbors the potential to provide ready access to these natural proteins as well as to create nonnatural ones with desirable attributes. During the previous grant period, new chemical means were discovered to manipulate protein structure and protein function.
Specific Aims. The overall goal of the proposed research is to use ideas and methods from organic chemistry and chemical biology to extend our fundamental understanding of the chemical reactivity of proteins, and to employ that understanding in meaningful ways. During the next grant period, this intent will be achieved in four Specific Aims.
Aims 1 -3 employ chemistry to effect the bioreversible modification of protein amino groups, carboxyl groups, and sulfhydryl groups.
Aim 4 integrates three state-of-the-art methods in protein chemistry (nonnatural amino acid mutagenesis, expressed protein ligation, and the traceless Staudinger ligation) to produce authentic ubiquitin conjugates and to use those conjugates to reveal key molecular aspects of protein degradation by the proteasome. Notably, the modifications in Aims 1 and 2 will provide distinct means to deliver proteins into human cells, and those in Aims 1-3 will be performed on an important tumor suppressor protein, PTEN. Significance. The results of the research proposed herein will provide new insight into the intrinsic and extrinsic chemical reactivity of proteins, as well as extend the capacity to access and manipulate proteins. The knowledge gained will have a broad and deep impact on biomedicine in this post-genomic era.
A protein is a gene-encoded string of amino acids that folds into a three-dimensional structure. Proteins perform the molecular functions that are necessary for life, including catalysis of biochemical reactions (by enzymes), neutralization of foreign toxis (by antibodies), and stimulation of cellular activity (by hormones). The goal of this project is to develop chemical means to manipulate proteins with a precision that is unobtainable with other (e.g., genetic) methods and to endow proteins thereby with desirable attributes that could be transformative to biomedicine.
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