Olivier Lichtarge, M.D., Ph.D.
Professor of Molecular and Human Genetics
Professor, Departments of Biochemistry & Molecular Biology and Pharmacology; Programs in Developmental Biology; Integrative Molecular and Biomedical Sciences; and Structural & Computational Biology and Molecular Biophysics
Director, Computational and Integrative Biomedical Research Center
B.S., McGill University, 1980
Ph.D., Stanford University, 1987
M.D., Stanford University, 1990
Residency, Internal Medicine, University of California, San Francisco, 1993
Fellowship, Endocrinology, University of California, San Francisco, 1996
Postdoc, University of California, San Francisco, 1997
Our lab marries computation with experiments to study three areas of protein structure-function: the molecular basis of protein catalysis and interaction, the design of peptides and proteins, and the annotation of protein sequence and structure. In each case, our long-term goals are to engineer proteins or peptides to probe and then rationally disrupt protein pathways.
To guide experiments, we rely on an integrated computational analysis of the evolution of protein sequences, structures, and functions. This phylogenomic strategy is called the Evolutionary Trace (ET) and, most simply, it assigns to each sequence residue a relative score of “functional importance”. From this we can formulate hypotheses on the molecular determinants of activity and specificity, and rationally target experiments to the most relevant sites of a protein.
In the G protein signaling pathway, one example of this approach is a G protein-coupled receptor engineered to signal through the ERK/MAPK pathway but not through the typical G protein mechanism (Shenoy et al., 2006). Another example is an RGS7 mutant designed to shut off G protein signaling as if it were an RGS9 (Sowa et al., 2001). Likewise in nuclear hormone receptors and bHLH transcription factors, targeted mutations enabled us to swap DNA binding (Raviscioni et al., 2005) and in vivo proneural development (Quan et al., 2004), respectively. Finally, Evolutionary Trace-based peptides let us mimic a protein-protein interaction surface and disrupt normal binding in Germ Cell Nuclear Transcription Factor (GCNF4).
Thus while our computational aims are to improve the general annotation of function on a proteomic scale, our experimental projects aim to characterize molecular mechanisms in protein families of intense pharmaceutical interest. The hope is that computation and design, together, can lead to novel drug targets and to novel approaches for the development of therapeutics.
- Amin SR, Erdin S, Ward RM, Lua RC, Lichtarge O (2013). Prediction and experimental validation of enzyme substrate specificity in protein structures. Proc. Natl. Acad. Sci. U S A. PubMed PMID: 24145433
- Adikesavan AK, Katsonis P, Marciano DC, Lua R, Herman C, Lichtarge O (2011). Separation of Recombination and SOS Response in Escherichia coli RecA Suggests LexA Interaction Sites. PLoS Genet. 7(9): e1002244. doi:10.1371/journal.pgen.1002244
- Rodriguez GJ, Yao R, Lichtarge O, Wensel TG (2010). Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors. Proc. Natl. Acad. Sci. U S A 107(17): 7787-92. PubMed PMID: 20385837
- Lichtarge O, Wilkins A (2010). Evolution: a guide to perturb protein function and networks. Curr. Opin. Struct. Biol. 20(3): 351-9. PubMed PMID: 20444593
- Erdin S, Ward RM, Venner E, Lichtarge O (2010). Evolutionary trace annotation of protein function in the structural proteome. J. Mol. Biol. 396(5): 1451-73. PubMed PMID: 20036248
- Ward RM, Erdin S, Tran TA, Kristensen DM, Lisewski AM, Lichtarge O (2008). De-Orphaning the Structural Proteome through Reciprocal Comparison of Evolutionarily Important Structural Features. PLoS ONE 3(5): e2136. PubMed PMID: 18461181
- Ribes-Zamora A, Mihalek I, Lichtarge O, Bertuch AA (2007). Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions. Nat. Struct. Mol. Biol. 14(4): 301-7. PubMed PMID: 17351632
- Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ (2006). Beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J. Biol. Chem. 281(2): 1261-73. PubMed PMID: 16280323
- Madabushi S, Gross AK, Philippi A, Meng EC, Wensel TG, Lichtarge O (2004). Evolutionary trace of G protein-coupled receptors reveals clusters of residues that determine global and class-specific functions. J. Biol. Chem. 279(9): 8126-32. PubMed PMID: 14660595
- Yao H*, Kristensen DM*, Mihalek I, Sowa ME, Shaw C, Kimmel M, Kavraki L, Lichtarge O (2003). An accurate, scalable method to identify functional sites in protein structures. J. Mol. Biol. 326(1): 255-61. PubMed PMID: 12547207
- Madabushi S, Yao H, Marsh M, Kristensen D, Philippi A, Sowa ME, Lichtarge O (2002). Structural Clusters of Evolutionary Trace Residues Are Statistically Significant and Common in Proteins. J. Mol. Biol. 316(1): 139-54. PubMed PMID: 11829509
- Sowa ME, Wei He, Slep KC, Kercher MA, Lichtarge O, Wensel TG (2001). Prediction and confirmation of an allosteric pathway for regulation of RGS domain activity. Nat. Struct. Biol. 8(3): 234-7. PubMed PMID: 11224568
Awards and Honors
2005: Raymond and Beverley Sackler Fellowship, IHES, France
2001: Basil O’Connor Award, March of Dimes
1999: American Heart Association, Faculty Development Award
1997: American Heart Association, Post-doctoral Fellowship
1995: Dorothy Penrose Stout Fellowship Award, American Heart Association, California Affiliate
Olivier Lichtarge M.D., Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.
Web site: Lichtarge Computational Biology Lab