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.
|Lavis, Luke D; Raines, Ronald T (2014) Bright building blocks for chemical biology. ACS Chem Biol 9:855-66|
|Lukesh 3rd, John C; Andersen, Kristen A; Wallin, Kelly K et al. (2014) Organocatalysts of oxidative protein folding inspired by protein disulfide isomerase. Org Biomol Chem 12:8598-602|
|Lukesh 3rd, John C; Wallin, Kelly K; Raines, Ronald T (2014) Pyrazine-derived disulfide-reducing agent for chemical biology. Chem Commun (Camb) 50:9591-4|
|Lukesh 3rd, John C; Vanveller, Brett; Raines, Ronald T (2013) Thiols and selenols as electron-relay catalysts for disulfide-bond reduction. Angew Chem Int Ed Engl 52:12901-4|
|Chou, Ho-Hsuan; Raines, Ronald T (2013) Conversion of azides into diazo compounds in water. J Am Chem Soc 135:14936-9|
|Marshall, Carrie J; Agarwal, Nitin; Kalia, Jeet et al. (2013) Facile chemical functionalization of proteins through intein-linked yeast display. Bioconjug Chem 24:1634-44|
|Aronoff, Matthew R; VanVeller, Brett; Raines, Ronald T (2013) Detection of boronic acids through excited-state intramolecular proton-transfer fluorescence. Org Lett 15:5382-5|
|Arnold, Ulrich; Huck, Bayard R; Gellman, Samuel H et al. (2013) Protein prosthesis: ?-peptides as reverse-turn surrogates. Protein Sci 22:274-9|
|Levine, Michael N; Hoang, Trish T; Raines, Ronald T (2013) Fluorogenic probe for constitutive cellular endocytosis. Chem Biol 20:614-8|
|Chao, Tzu-Yuan; Raines, Ronald T (2013) Fluorogenic label to quantify the cytosolic delivery of macromolecules. Mol Biosyst 9:339-42|
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