Matt is fascinated by how macromolecules are able to specifically recognize each other and form functional complexes in the crowded cellular milieu. Many years of molecular, biophysical and structural studies have revealed a broad array of strategies that are currently employed by proteins and nucleic acids to create specific molecular recognition interfaces. Indeed, during his graduate work on HIV Rev, Matt became very interested in how structural adaptability of simple three-dimensional motifs, such as a helix-loop-helix domain, can be employed to define the specificity of binding. What is not obvious is how the fourth dimension, that of evolutionary time, plays into how recognition surfaces are created and maintained. One implication of his graduate work was that HIV, and likely many other viruses, use recognition strategies that are highly ‘evolvable’ by being able to tolerate and even benefit from the high viral mutation rate. In the Malik lab, he is interested in the evolvability of recognition surfaces used by the innate immune system, and will ask what strategies are employed to defeat viruses. He is particularly interested in using signatures of evolution to gain molecular insight into how viruses are recognized by the innate immune system and how they evade detection. He is excited to think about these problems from an evolutionary, molecular and structural perspective.
Daugherty, M.D. & Malik, H.S. Rules of engagement: molecular insights from host-virus arms races. Annu Rev Genet In press (2012).
Daugherty, M.D., Liu, B. & Frankel, A.D. Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. Nat Struct Mol Biol 17, 1337-42 (2009).
Daugherty, M.D., Booth, D.S., Jayaraman, B., Cheng, Y. & Frankel, A.D. HIV Rev response element (RRE) directs assembly of the Rev homooligomer into discrete asymmetric complexes. Proc Natl Acad Sci U S A 107, 12481-86 (2009).
Daugherty, M.D., D'Orso, I. & Frankel, A.D. A solution to limited genomic capacity: using adaptable binding surfaces to assemble the functional HIV Rev oligomer on RNA. Mol Cell 31, 824-34 (2008).
Mills, N.L., Daugherty, M.D., Frankel, A.D. & Guy, R.K. An alpha-helical peptidomimetic inhibitor of the HIV-1 Rev-RRE interaction. J Am Chem Soc 128, 3496-7 (2006).
Calabro, V., Daugherty, M.D. & Frankel, A.D. A single intermolecular contact mediates intramolecular stabilization of both RNA and protein. Proc Natl Acad Sci U S A 102, 6849-54 (2005).
Daugherty, M. et al. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem 277, 21431-9 (2002).
Daugherty, M., Vonstein, V., Overbeek, R. & Osterman, A. Archaeal shikimate kinase, a new member of the GHMP-kinase family. J Bacteriol 183, 292-300 (2001).
Zhou, T., Daugherty, M., Grishin, N.V., Osterman, A.L. & Zhang, H. Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily. Structure 8, 1247-57 (2000).