Vanderbilt University School of Medicine

Lacy, D. Borden , Ph.D.
Associate Professor of Pathology, Microbiology and Immunology
Associate Professor of Biochemistry

Lab Url: N/A

Phone Number: 615-343-9080

Email Address:borden.lacy@vanderbilt.edu

Lacy, D. Borden's picture

Office Address   Mailing Address

A4116A MCN

A-5301 MCN 37232


Research Keywords
bacterial protein toxins, host responses to bacterial pathogens, Clostridium difficile, structural biology,Bacteria,Biochemistry,Infectious disease,Microbiology,Protein Structure,Receptor

Research Specialty
Understanding the structures and mechanisms of bacterial protein toxins and their host interactions

Research Description
Pathogenic bacteria have evolved a diverse array of mechanisms for delivering toxins and other virulence factors into the interior of host cells. Studying the molecular structures of these virulence factors alone and in complex with host receptors, membranes, and inhibitors can lend insight into how these delivery processes occur and how these processes can be exploited or prevented. Current research in the Lacy laboratory is primarily focused on the structure and function of large clostridial cytotoxins, including the two toxins responsible for symptoms in C. difficile infection. Structural biology is combined with cellular and animal models of intoxication and infection to understand the toxin-host interaction at the molecular level. In addition, we aim to identify new toxin inhibitors using both rational design and high-throughput screening approaches.

Publications
LaFrance, ME, Farrow, MA, Chandrasekaran, R, Sheng, J, Rubin, DH, Lacy, DB. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. Proc Natl Acad Sci U S A, 112(22), 7073-8, 2015.

Varela Chavez, C, Hoos, S, Haustant, GM, Chenal, A, England, P, Blondel, A, Pauillac, S, Lacy, DB, Popoff, MR. The catalytic domains of Clostridium sordellii lethal toxin and related large clostridial glucosylating toxins specifically recognize the negatively charged phospholipids phosphatidylserine and phosphatidic acid. Cell Microbiol, , , 2015.

Wang, X, Yamamoto, Y, Wilson, LH, Zhang, T, Howitt, BE, Farrow, MA, Kern, F, Ning, G, Hong, Y, Khor, CC, Chevalier, B, Bertrand, D, Wu, L, Nagarajan, N, Sylvester, FA, Hyams, JS, Devers, T, Bronson, R, Lacy, DB, Ho, KY, Crum, CP, McKeon, F, Xian, W. Cloning and variation of ground state intestinal stem cells. Nature, 522(7555), 173-8, 2015.

Dumont, AL, Yoong, P, Liu, X, Day, CJ, Chumbler, NM, James, DB, Alonzo, F, Bode, NJ, Lacy, DB, Jennings, MP, Torres, VJ. Identification of a Crucial Residue Required for Staphylococcus aureus LukAB Cytotoxicity and Receptor Recognition. Infect Immun, 82(3), 1268-76, 2014.

Zhang, Z, Park, M, Tam, J, Auger, A, Beilhartz, GL, Lacy, DB, Melnyk, RA. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. Proc Natl Acad Sci U S A, , , 2014.

Benefield, DA, Dessain, SK, Shine, N, Ohi, MD, Lacy, DB. Molecular assembly of botulinum neurotoxin progenitor complexes. Proc Natl Acad Sci U S A, 110(14), 5630-5, 2013.

Farrow, MA, Chumbler, NM, Lapierre, LA, Franklin, JL, Rutherford, SA, Goldenring, JR, Lacy, DB. Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. Proc Natl Acad Sci U S A, , , 2013.

Reyes-Robles, T, Alonzo, F, Kozhaya, L, Lacy, DB, Unutmaz, D, Torres, VJ. Staphylococcus aureus Leukotoxin ED Targets the Chemokine Receptors CXCR1 and CXCR2 to Kill Leukocytes and Promote Infection. Cell Host Microbe, 14(4), 453-9, 2013.

Slater, LH, Hett, EC, Mark, K, Chumbler, NM, Patel, D, Lacy, DB, Collier, RJ, Hung, DT. Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death. ACS Chem Biol, 8(4), 812-22, 2013.

Chambers, MG, Pyburn, TM, Gonzalez-Rivera, C, Collier, SE, Eli, I, Yip, CK, Takizawa, Y, Lacy, DB, Cover, TL, Ohi, MD. Structural Analysis of the Oligomeric States of Helicobacter pylori VacA Toxin. J Mol Biol, , , 2012.

Chumbler, NM, Farrow, MA, Lapierre, LA, Franklin, JL, Haslam, D, Goldenring, JR, Lacy, DB. Clostridium difficile Toxin B Causes Epithelial Cell Necrosis through an Autoprocessing-Independent Mechanism. PLoS Pathog, 8(12), e1003072, 2012.

Pruitt, RN, Chumbler, NM, Rutherford, SA, Farrow, MA, Friedman, DB, Spiller, B, Lacy, DB. Structural determinants of Clostridium difficile toxin A glucosyltransferase activity. J Biol Chem, 287(11), 8013-20, 2012.

Pruitt, RN, Lacy, DB. Toward a structural understanding of Clostridium difficile toxins A and B. Front Cell Infect Microbiol, 2, 28, 2012.

Johnson, PM, Chen, SS, Santomango, TS, Williams, PE, Lacy, DB, McGuinness, OP. Continuous low-dose fructose infusion does not reverse glucagon-mediated decrease in hepatic glucose utilization. Metabolism, 60(6), 867-73, 2011.

Mushrush, DJ, Koteiche, HA, Sammons, MA, Link, AJ, McHaourab, HS, Lacy, DB. Studies of the Mechanistic Details of the pH-dependent Association of Botulinum Neurotoxin with Membranes. J Biol Chem, 286(30), 27011-8, 2011.

Gangwer, KA, Shaffer, CL, Suerbaum, S, Lacy, DB, Cover, TL, Bordenstein, SR. Molecular evolution of the Helicobacter pylori vacuolating toxin gene (vacA). J Bacteriol, , , 2010.

Gonz?!lez-Rivera, C, Gangwer, KA, McClain, MS, Eli, IM, Chambers, MG, Ohi, MD, Lacy, DB, Cover, TL. Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry, 49(27), 5743-52, 2010.

Ivie, SE, McClain, MS, Algood, HM, Lacy, DB, Cover, TL. Analysis of a beta-helical region in the p55 domain of Helicobacter pylori vacuolating toxin. BMC Microbiol, 10, 60, 2010. PMCID:2836311

Pruitt, RN, Chambers, MG, Ng, KK, Ohi, MD, Lacy, DB. Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A, 107(30), 13467-72, 2010.

Schmitt, J, Karalewitz, A, Benefield, DA, Mushrush, DJ, Pruitt, RN, Spiller, BW, Barbieri, JT, Lacy, DB. Structural analysis of botulinum neurotoxin type G receptor binding . Biochemistry, 49(25), 5200-5, 2010.

Chen, SS, Santomango, TS, Williams, PE, Lacy, DB, McGuinness, OP. Glucagon-mediated impairments in hepatic and peripheral tissue nutrient disposal are not aggravated by increased lipid availability. Am J Physiol Endocrinol Metab, 296(5), E1172-8, 2009.

Pruitt, RN, Chagot, B, Cover, M, Chazin, WJ, Spiller, B, Lacy, DB. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J Biol Chem, 284(33), 21934-40, 2009.

Fischer, A, Mushrush, DJ, Lacy, DB, Montal, M. Botulinum neurotoxin devoid of receptor binding domain translocates active protease. PLoS Pathog, 4(12), e1000245, 2008. PMCID:2596314

Ivie, SE, McClain, MS, Torres, VJ, Algood, HM, Lacy, DB, Yang, R, Blanke, SR, Cover, TL. Helicobacter pylori VacA subdomain required for intracellular toxin activity and assembly of functional oligomeric complexes. Infect Immun, 76(7), 2843-51, 2008. PMCID:2446698

Gangwer, KA, Mushrush, DJ, Stauff, DL, Spiller, B, McClain, MS, Cover, TL, Lacy, DB. Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc Natl Acad Sci U S A, 104(41), 16293-8, 2007. PMCID:2042200

Scobie, HM, Marlett, JM, Rainey, GJ, Lacy, DB, Collier, RJ, Young, JA. Anthrax toxin receptor 2 determinants that dictate the pH threshold of toxin pore formation. PLoS ONE, 2, e329, 2007. PMCID:1824706

Melnyk, RA, Hewitt, KM, Lacy, DB, Lin, HC, Gessner, CR, Li, S, Woods, VL, Collier, RJ. Structural determinants for the binding of anthrax lethal factor to oligomeric protective antigen. J Biol Chem, 281(3), 1630-5, 2006.

Scobie, HM, Wigelsworth, DJ, Marlett, JM, Thomas, D, Rainey, GJ, Lacy, DB, Manchester, M, Collier, RJ, Young, JA. Anthrax Toxin Receptor 2-Dependent Lethal Toxin Killing In Vivo. PLoS Pathog, 2(10), , 2006. PMCID:1617126

Krantz, BA, Melnyk, RA, Zhang, S, Juris, SJ, Lacy, DB, Wu, Z, Finkelstein, A, Collier, RJ. A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Science, 309(5735), 777-81, 2005. PMCID:1815389

Lacy, DB, Lin, HC, Melnyk, RA, Schueler-Furman, O, Reither, L, Cunningham, K, Baker, D, Collier, RJ. A model of anthrax toxin lethal factor bound to protective antigen. Proc Natl Acad Sci U S A, 102(45), 16409-14, 2005. PMCID:1283467

Lacy, DB, Wigelsworth, DJ, Melnyk, RA, Harrison, SC, Collier, RJ. Structure of heptameric protective antigen bound to an anthrax toxin receptor: a role for receptor in pH-dependent pore formation. Proc Natl Acad Sci U S A, 101(36), 13147-51, 2004. PMCID:516539

Lacy, DB, Wigelsworth, DJ, Scobie, HM, Young, JA, Collier, RJ. Crystal structure of the von Willebrand factor A domain of human capillary morphogenesis protein 2: an anthrax toxin receptor. Proc Natl Acad Sci U S A, 101(17), 6367-72, 2004. PMCID:404051

Wigelsworth, DJ, Krantz, BA, Christensen, KA, Lacy, DB, Juris, SJ, Collier, RJ. Binding stoichiometry and kinetics of the interaction of a human anthrax toxin receptor, CMG2, with protective antigen. J Biol Chem, 279(22), 23349-56, 2004.

Mourez, M, Yan, M, Lacy, DB, Dillon, L, Bentsen, L, Marpoe, A, Maurin, C, Hotze, E, Wigelsworth, D, Pimental, RA, Ballard, JD, Collier, RJ, Tweten, RK. Mapping dominant-negative mutations of anthrax protective antigen by scanning mutagenesis. Proc Natl Acad Sci U S A, 100(24), 13803-8, 2003. PMCID:283502

Cunningham, K, Lacy, DB, Mogridge, J, Collier, RJ. Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen. Proc Natl Acad Sci U S A, 99(10), 7049-53, 2002. PMCID:124526

Lacy, DB, Collier, RJ. Structure and function of anthrax toxin. Curr Top Microbiol Immunol, 271, 61-85, 2002.

Lacy, DB, Mourez, M, Fouassier, A, Collier, RJ. Mapping the anthrax protective antigen binding site on the lethal and edema factors. J Biol Chem, 277(4), 3006-10, 2002.

Mogridge, J, Cunningham, K, Lacy, DB, Mourez, M, Collier, RJ. The lethal and edema factors of anthrax toxin bind only to oligomeric forms of the protective antigen. Proc Natl Acad Sci U S A, 99(10), 7045-8, 2002. PMCID:124525

Mourez, M, Lacy, DB, Cunningham, K, Legmann, R, Sellman, BR, Mogridge, J, Collier, RJ. 2001: a year of major advances in anthrax toxin research. Trends Microbiol, 10(6), 287-93, 2002.

Pannifer, AD, Wong, TY, Schwarzenbacher, R, Renatus, M, Petosa, C, Bienkowska, J, Lacy, DB, Collier, RJ, Park, S, Leppla, SH, Hanna, P, Liddington, RC. Crystal structure of the anthrax lethal factor. Nature, 414(6860), 229-33, 2001.

Lacy, DB, Stevens, RC. Sequence homology and structural analysis of the clostridial neurotoxins. J Mol Biol, 291(5), 1091-104, 1999.

Lacy, DB, Stevens, RC. Unraveling the structures and modes of action of bacterial toxins. Curr Opin Struct Biol, 8(6), 778-84, 1998.

Lacy, DB, Tepp, W, Cohen, AC, DasGupta, BR, Stevens, RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol, 5(10), 898-902, 1998.

Lacy, DB, Stevens, RC. Recombinant expression and purification of the botulinum neurotoxin type A translocation domain. Protein Expr Purif, 11(2), 195-200, 1997.

McGuinness, OP, Lacy, DB, Ejiofor, J, Bagby, GG. Hepatic release of tumor necrosis factor in the endotoxin-treated conscious dog. Shock, 5(5), 344-8, 1996.

Crimmins, MT, Huang, S, Guise, LE, Lacy DB. Addition of functionalized zinc copper reagents to acetylenic esters: synthesis of 2-carboalkoxy cyclohexenones. Tetrahedron Letters, 36, 7061-64, 1995.


Postdoctoral Position Available
Yes

Postdoctoral Position Details
please inquire

Updated Date
08/19/2015



Vanderbilt University is committed to principles of equal opportunity and affirmative action.
Copyright 2008 Vanderbilt University School of Medicine
The office of Biomedical Research Education & Training All rights reserved.
For questions or problems concerning this page, please submit a help ticket.