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Alexander Research Group
|Understanding protein-nucleic acid interactions at the molecular level|
Although the basic mechanisms of protein synthesis are established and structures of many of the components have been determined, details remain unknown at the molecular level. Not only are the mechanisms of protein synthesis worth investigating at the level of basic research, but they provide many targets for design and development of new drugs. Because translation is an essential function in all organisms, inhibitors of protein synthesis are among the most common drugs in use today. The projects in our lab use a variety of techniques (protein engineering, kinetic analysis, binding studies, PCR amplification, nucleic acid synthesis and purification, and spectroscopy) to answer biochemical questions on a molecular level. We also have collaborations with researchers who use X-ray crystallography, mass spectrometry, and bacterial and mammalian cellular analyses to probe molecular mechanisms.
Contribution of conformational flexibility to chemical catalysis
The side-effects of accuracy control
The impact of minor-groove DNA adducts on cellular processes
We have been collaborating with Dr. Uli Bierbach (WFU Chemistry) to study the molecular effects of treating DNA with the novel platinum-containing compound PT-ACRAMTU. We have confirmed using restriction enzyme analyses and transcriptional footprinting that PT-ACRAMTU modifies A bases in TpA and GpA steps. Covalent modification inhibits T7 RNA polymerase from transcribing DNA, which may point to a mechanism for its demonstrated activity against cancer cells. Electrophoretic mobility shift assays with the TATA-binding protein (TBP) demonstrated that adducts formed at the N3 position of adenine are most effective at blocking TBP binding and probably represent the physiologically relevant adduct. We will continue to probe the molecular impact of DNA damage using the tools of biochemistry and molecular biology.
Characterizing a cold-induced RNA helicase
M.E. Budiman, U. Bierbach, and R.W. Alexander (2005) “DNA minor groove adducts formed by a platinum-acridine conjugate inhibit association of TATA-binding protein with its cognate sequence.” Biochemistry44, 11262-11268.
M.E. Budiman, R.W. Alexander, and U. Bierbach (2004) “Unique base-step recognition by a platinum-acridinylthiourea conjugate leads to a DNA damage profile complementary to that of the anticancer drug cisplatin.” Biochemistry43, 8560-8567.
R.W. Alexander, and K. Tamura (2004) “Peptide synthesis through evolution.” Cell. Mol. Life Sci.61, 1317-1330.
R.W. Alexander, and P. Schimmel (2001) “Domain-domain communication in aminoacyl-tRNA synthetases.” Prog. Nucl. Acid Res. Mol. Biol. 69, 317-349.
R.W. Alexander and P. Schimmel (2002) "Protein synthesis." In Encyclopedia of Physical Science and Technology (Robert A. Myers, ed.) 3 rd ed., Vol. 13. Academic Press ( San Diego, CA), 219-240.
R.W. Alexander and P. Schimmel (2000) "Multifunctional proteins." In McGraw-Hill 2001 Yearbook of Science & Technology, McGraw-Hill ( New York, NY), pp.265-266.
B. S. Cooperman, R. W. Alexander, Y. Bukhtiyarov, S. N. Vladimirov, Z. Druzina, R. Wang, and N. Zuno (2000) "Photolabile derivatives of oligonucleotides (PHONTs) as probes of ribosomal structure." Methods Enzymol. 318, 118-136.
R.W. Alexander and P. Schimmel (1999) "Evidence for breaking domain-domain functional communication in a synthetase-tRNA complex." Biochemistry38, 16359-16365.
R. Wang, R.W. Alexander, M. van Loock, S. Vladimirov, Y. Bukhtiyarov, S.C. Harvey, and B.S. Cooperman (1999) "Three-dimensional placement of the conserved 530 loop of 16 S rRNA and of its neighboring components in the 30 S subunit." J. Mol. Biol. 286, 521-540.
R.W. Alexander, B.E. Nordin, and P. Schimmel (1998) "Activation of microhelix charging by localized helix destabilization." Proc. Natl. Acad. Sci. USA95, 12214-12219.
P. Schimmel and R.W. Alexander (1998) "Diverse RNA substrates for aminoacylation: clues to origins?" Proc. Natl. Acad. Sci. USA 95, 10351-10353.
P. Schimmel and R.W. Alexander (1998) "All you need is RNA." Science 281, 658-659.