Faculty & Staff
Title/s: Assistant Professor
Office #: FH-422
- 1988 B.S., Wuhan University, China
- 2001 Ph.D., University of Oklahoma
- 2002-2003 Postdoctoral Fellow, University of Oklahoma
- 2003-2004 Postdoctoral Fellow, UT Southwestern Medical Center at Dallas
- 2004-2009 Postdoctoral Fellow, Brandeis University
Dr. Liu’s laboratory employs X-ray crystallography, mechanistic studies, biological assays, and computer simulations to study key protein components involved in bacterial pathogenesis and human diseases. Following the doctrine of “Structure Determines Function”, our research evolves around identifying key protein structures that are mechanistically relevant to the biochemical processes. Puzzling together these relevant structures like snapshots, we gain knowledge on sophisticated biological functions; we aim to apply that knowledge to discover novel antimicrobial methods and conduct structure-based drug design.
Current research areas include:
1. Structural Enzymology of the Quorum-Quenching Enzymes, Lactonases and Acylases.
Bacterial cells coordinate their gene regulation critical to colonization, biolfilm formation, virulence and survival in competitive environments through Quorum Sensing. Enzymes capable of disrupting quorum sensing are called quorum-quenching enzymes. We have been studying the catalysis, specificity, and biological functions of two quorum-quenching catalysts lactonase and acylase, in particular their roles disrupting the quorum-sensing pathways of the competing microorganisms. The obtained knowledge can potentially generate novel methods to combat persistent infections via blocking or disrupting the quorum-sensing pathways of the pathogenic bacteria.
For Lactonase: Using mechanistic crystallography, we start to “paint” a picture of the overall lactonase (AiiA) catalysis. We are also working on the enzyme specificity as well as promiscuity of the lactonases including AiiA, AiiB, AttM and AidC. Based on this knowledge, we are currently on to protein engineering to change enzyme specificity and evaluate the antimicrobial potential of the lactonases.
For Acylase: Acylase PvdQ isolated from pseudomonas aeruginosa is an Ntn (N-terminal nucleophile) hydrolase requires post-translational processing to be active. Furthermore, it is also at the nexus between Quorum Sensing and Siderophore Biosynthesis, which both could be critical for bacterial survival and virulence expression. In collaboration with other research groups, we are set to unveil the catalytic mechanism and substrate specificity of the PvdQ and unveil its detailed biological significance in both quorum quenching and siderophore biosynthesis. Our recent work includes inhibitor design using a transition-state analog as a “warhead” and proposition of a revised catalytic mechanism based on the complex structure of PvdQ and the identified transition state analog.
2. The Bacterial Transcription Regulator GabR.
A evolutionary fusion of a PLP-dependent enzyme and a DNA binding domain, GabR is evolved to control the expression of two enzymes that are key in bacterial stress resistance as well as nitrogen metabolism. We have solved a novel structure of GabR; the solved crystal structure of a head-to-tail dimer implicates various possibilities in regulation mechanism. Understanding the GabR-dependent regulation on the “GABA shunt” pathway in bacteria will leads to discovering the ligands to the regulation domain that can control bacterial stress response and, furthermore, pathogenicity. In collaboration with several other research groups, we are launching a combined effort using various biological assays, biochemical assays, and X-ray crystallography to unveil the regulation mechanism in GabR-dependent transcription regulation and its role in control bacterial stress resistance and virulence expression.
3. Structure-based Drug Design. We are providing structural support for several structural design efforts both within the Department and with other research groups nation wide. We employ both fragment based crystallization screen and mechanistic crystallography to identify the binding site, to elucidate the drug mechanism, and ultimately, to help design better drugs based on structural information. Current drug target include Acylase and human GABA aminotransferase et al.
- Jingling Liao, Chungxiang Wu, Christopher Burlak, Sheng Zhang, Heather Sahm, Mu Wang,Zhong-Yin Zhang, Kurt W. Vogel, Steven M Riddle, Mark Federici, Jeremy Nichols, Dali Liu, Mark Cookson, Todd A. Stone and Quyen Q. Hoang, (2014) The Parkinson's disease-associated mutation R1441H in LRRK2 prolongs the “active-state” of its GTPase domain, Proc. Natl. Acad. Sci. , 111, in press.
- Salette Martine1, Rui Wu1, Ruslan Sanishvili, Dali Liu, and Richard C Holz, (2014)The active site sulfenic acid ligand in nitrile hydratases can cunction as a nucleophile, J. Am. Chem. Soc., 136(4), 1186-1189.
- Raji Edayathumangalam1, Rui Wu1, Yuguang Wang, Roman Garcia, Wei Wang, Cheryl Kreinbring, Jingling Liao, Todd Stone, Quyen Q. Hoang, Boris Belitsky, Gregory A Petsko, Dagmar Ringe*, and Dali Liu* (2013) The crystal structure of GabR, a PLP-dependent bacterial transcription regulator Proc. Natl. Acad. Sci. Published Ahead of Print doi 10.1073/pnas1315887110
- Wade C. McGregor, Danuta M Gillner, Sabina I. Swierczek, Dali Liu and Richard C. Holz (2013) Identification of a Histidine Metal Ligand in the argE-Encoded N-Acetyl-L-Ornithine SpringerPlus 2013, 2:482 doi:10.1186/2193-1801-2-482
- Kenneth Clevenger, Rui Wu, Joyce Er, Dali Liu* and Walter Fast* (2013) Rational design of a transition state analog with picomolar affinity for Pseudomonas aeruginosa PvdQ, a siderophore biosynthetic enzyme ACS Chem. 8(10), 2192-2200
- Ce-Feng Liu, Dali Liu, Jessica Momb, Pei W. Thomas, Ashley Lajoie, Gregory A. Petsko, Walt Fast, and Dagmar Ringe, (2013) A Distal Phenylalanine Clamp Controls Substrate Specificity in the Quorum-Quenching Metallo-g-lactonase (AiiA) from Bacillus thuringiensis. Biochemistry, 52(9), 1603-1610
- Misty L. Kuhn, Salette Martinez, Natalie Gumataotao, Uwe Bornscheuer, Dali Liu*, Richard C. Holz* (2012) The Fe-Type Nitrile Hydratase from Comamonas testosteroni Ni1 Does Not Require an Activator Accessory Protein for Expression in Escherichia coli. Biochem. Biophys. Res. Commun. 424(3): 365-370.
- Thomas, Pei; Zheng, Min; Wu, Shanshan; Guo, Hua; Liu, Dali*; Xu, Dingguo*; Fast, Walter*. (2011)Characterization of Purified New Delhi Metallo-β-Lactamase-1 (NDM-1), Biochemistry, 50(46): 10102-10113.
- Dali Liu, Edwin Pozharski, Mengmeng Fu, Richard B. Silverman, Dagmar Ringe. (2010)Mechanism of inactivation of E. coli aspartate aminotransferase by (S)-4-amino-4,5-dihydro-2-furancarboxylic acid (SADFA). Biochemistry, 49(49): 10507-10515.
- Bryan W. Lepore, Dali Liu, Ying Peng, Mengmeng Fu, Chad Yasuda, James M Manning, Richard B. Silverman, Dagmar Ringe. (2010) Chiral discrimination among aminotransferases: inactivation by 4-amino-4,5-dihydrothiophenecarboxylic acid. Biochemistry, 49(14): 3138-3147.