We look at life at the atomic level. To that end, we use high-resolution techniques, primarily X-ray crystallography, but also nuclear magnetic resonance spectroscopy (NMR), to determine the three-dimensional structures of proteins and protein complexes. In addition, we employ a variety of biophysical techniques, combined with the power of mutagenesis studies, to investigate static and dynamic aspects of regulation, enzymatic mechanism, protein-protein interactions, and drug design.
As part of the UTSW core labs, we specialize in collaborating with researchers on campus, thus combining the expertise of our collaborators in their respective fields with our expertise in structural biology. This model allows us to tackle complicated biological problems in a comprehensive way involving many different approaches and techniques.
Current projects include:
Enzymatic and regulatory mechanisms that alpha-ketoacid dehydrogenase multi-enzyme complexes (such as pyruvate dehydrogenase) used to funnel reaction products from glycolysis and amino acid metabolism into the Krebs cycle (collaboration with Dr. David Chuang, Dept. of Biochemistry).
Molecular mechanisms of neurotransmitter release (collaboration with Dr. Josep Rizo, Dept. of Biochemistry). A combination of techniques including X-ray crystallography and NMR is used to study proteins and protein-protein interactions involved in the release of neurotransmitters.
Lipoproteins from the bacterium T. pallidum, the causative agent for syphilis (collaboration with Dr. Michael Norgard, Dept. of Microbiology). Techniques derived from high-throughput structural genomics are used to decipher the function of a class of proteins from an organism that cannot be cultivated in vitro and is therefore not amenable to functional studies using classical biochemical and genetic methods.
Other projects include:
Molecular mechanisms of proteins involved in histone demethylation (collaboration with Dr. Hongtao Yu, Dept. of Pharmacology).
Molecular mechanisms of proteins involved in the spindle checkpoint (collaboration with Dr. Xuelian Luo, Dept. of Pharmacology).
Molecular mechanisms of actin polimerization (collaboration with Dr. Michael Rosen, Dept. of Biochemistry).
Molecular mechanisms of cystic fibrosis transmembrane conductance regulator (CFTR) (collaboration with Dr. Philip Thomas, Dept. of Physiology).
Molecular mechanisms of proteins involved in hypoxia response (collaboration with Dr. Kevin Gardner, Dept. of Biochemistry).
In addition, personal interests include genetic engineering of proteins to improve catalytic competence and thermostability, fundamental mechanisms of protein crystal growth, and structure and function of proteins involved in DNA repair
RESEARCH INTERESTS
Structural Biology
X-Ray Crystallography
DNA Repair
Protein Folding
Protein Engineering
RECENT PUBLICATIONS
Guan, R., Dai, H., Tomchick, D.R., Dulubova, I., Machius, M., Sudhof, T.C., Rizo, J., "Crystal Structure of the RIM1alpha C(2)B Domain at 1.7 ? Resolution" Biochemistry, 46:8988-8998, August 2007
Yang, M., Culhane, J.C., Szewczuk, L.M., Jalili, P., Ball, H.L., Machius, M., Cole, P.A., Yu, H., "Structural Basis for the Inhibition of the LSD1 Histone Demethylase by the Antidepressant trans-2-Phenylcyclopropylamine" Biochemistry, 46:8058-8065, July 2007
Yang, M., Culhane, J.C., Szewczuk, L.M. Gocke, C.B., Brautigam, C.A., Tomchick, D.R., Machius, M., Cole, P.A., Yu, H., "Structural basis of histone demethylation by LSD1 revealed by suicide inactivation" Nat. Struct. Mol. Biol., 14:535-539, June 2007
Li, J., Machius, M., Chuang, J.L., Wynn, R.M., Chuang, D.T., "The Two Active Sites in Human Branched-chain α-Keto Acid Dehydrogenase Operate Independently without an Obligatory Alternating-site Mechanism" J. Biol. Chem., 282:11904-11913, April 2007
Chosed, R., Tomchick, D.R., Brautigam, C.A., Mukherjee, S., Negi, V.S., Machius, M., Orth, K., "Structural analysis of Xanthomonas XopD provides insights into substrate specificity of ULPs" J. Biol. Chem., 282:6773-6782, March 2007
SIGNIFICANT PUBLICATIONS
Yang, M., Culhane, J.C., Szewczuk, L.M. Gocke, C.B., Brautigam, C.A., Tomchick, D.R., Machius, M., Cole, P.A., Yu, H., "Structural basis of histone demethylation by LSD1 revealed by suicide inactivation" Nat. Struct. Mol. Biol., 14:535-539, June 2007
Yang, M., Culhane, J.C., Szewczuk, L.M. Gocke, C.B., Brautigam, C.A., Tomchick, D.R., Machius, M., Cole, P.A., Yu, H., "Structural basis of histone demethylation by LSD1 revealed by suicide inactivation" Nat. Struct. Mol. Biol., 14:535-539, June 2007
Yang, M., Gocke, C.B., Luo, X., Borek, D., Tomchick, D.R., Machius, M., Otwinowski, Z., Yu, H., "Structural Basis for CoREST-Dependent Demethylation of Nucleosomes by the Human LSD1 Histone Demethylase" Mol. Cell, 23:377-387, August 2006
Otomo, T., Tomchick, D.R., Otomo, C., Panchal, S.C., Machius, M., Rosen, M.K., "Structural basis for actin filament nucleation and processive capping by a formin homology 2 domain" Nature, 433:488-494, February 2005
Machius, M., Wynn, R.M., Chuang, J.L., Li, J., Kluger, R., Yu, D., Tomchick, D.R., Brautigam, C.A., Chuang, D.T., "A versatile conformational switch regulates reactivity in human branched-chain α-ketoacid dehydrogenase" Structure, 14:287-298, February 2006
Thibodeau, P.H., Brautigam, C.A., Machius, M., Thomas, P.J., "Side chain and backbone contributions of Phe508 to CFTR folding" Nat. Struct. Mol. Biol., 12:10-16, January 2005
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