个人简介

Education: PhD - University of North Carolina, Chapel Hill BS - North Carolina State University

研究领域

Synthesis/Biomolecular Structure and Function/Biological/Organic

Our research interests are broadly based in chemical biology, mechanistic enzymology and molecular medicine. Towards this end our group is engaged in understanding the chemical and kinetic mechanisms, substrate specificity and therapeutic importance of enzymes that posttranslationally modify chromatin, such as histone deacetylases, histone demethylases, histone methyl transferases, and chromatin assembly and remodeling complexes. Building on a mechanistic foundation, our laboratory is also interested in the design, chemical synthesis and evaluation of small molecules to modulate the activity of chromatin modifying enzymes within living cells. This work has recently led to the discovery of histone deamethylases as potential targets for anti-depression therapy. In addition, our laboratory also works to identify and develop novel strategies to overcome bacterial resistance to antibiotics through mechanistic characterization of enzymes involved in bacterial virulence, peptidoglycan biosynthesis, and teichoic acid biosynthesis. A central component of this research is the identification of novel anti-virulence chemotherapeutics and antibiotics capable of overcoming infections from antibiotic resistant bacteria. Our group also works to decode the molecular mechanisms of enzymes involved in mechanistically intriguing reactions from antibiotic natural product biosynthesis. Lastly, our group is working to develop a functional view of the molecular underpinning of initial signaling events in bacterial-induced inflammation, and in turn lay the foundation for the discovery and design of novel small molecule inhibitors of Crohn's disease, ulcerative colitis and related inflammatory bowel disorders.

近期论文

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Qi Y, Amiram M, Gao W, McCafferty DG, Chilkoti A. (2013) Sortase-Catalyzed Initiator Attachment Enables High Yield Growth of a Stealth Polymer from the C Terminus of a Protein. Macromol. Rapid Commun. 2013 Aug;34(15):1256-1260. Melvin JA, McCafferty DG. Chapter 551. (2013) Sortases. In Handbook of Proteolytic Enzymes, 3rd ed.; Smaldon W, Rawlings ND, Salvesen G, Eds.; Academic Press: New York. 2013 May;3(2):2459-2465 Bellucci JJ, Amiram M, Bhattacharyya J, McCafferty D, Chilkoti A. (2013) Three-in-One Chromatography-Free Purification, Tag Removal, and Site-Specific Modification of Recombinant Fusion Proteins Using Sortase A and Elastin-like Polypeptides Angew. Chem. Int. Ed. 2013 Mar 25;52(13):3703-3708. Folk DS, Torosian JC, Hwang S, McCafferty DG, Franz KJ. (2012) Monitoring B-Secretase Activity in Living Cells with a Membrane Anchored FRET Probe. Angew. Chem. Int. Ed. 2012 Oct 22;51(43):10795-9. Weinberg DR, Gagliardi CJ, Hull JF, Murphy CF, Kent CA, Westlake BC, Paul A, Ess DH, McCafferty DG, Meyer TJ. (2012) Proton-Coupled Electron Transfer. Chem Rev. 2012; 112(7):4016-4093. Pollock JA, Larrea MD, Jasper JS, McDonnell DP, McCafferty DG. (2012) Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERa-dependent and independent manners. ACS Chem Biol. 2012 Jul 20; 7(7):1221-1231 Hoertz AJ, Hamburger JB, Gooden DM, Bednar MM, McCafferty DG. (2012) Studies on the biosynthesis of the lipodepsipeptide antibiotic Ramoplanin A2. Bioorg Med Chem. 2012 Jan 15; 20(2):859-865. Bednar MM, Jorgensen I, Valdivia RH, McCafferty DG. (2011) Chlamydia protease-like activity factor (CPAF): characterization of proteolysis activity in vitro and development of a nanomolar affinity CPAF zymogen-derived inhibitor. Biochemistry. 2011 Sep 6; 50(35):7441-7443. Jorgensen I, Bednar MM, Amin V, Davis BK, Ting JP, McCafferty DG, Valdivia RH. (2011) The Chlamydia protease CPAF regulates host and bacterial proteins to maintain pathogen vacuole integrity and promote virulence. Cell Host Microbe. 2011 Jul 21; 10(1):21-32. Melvin JA, Murphy CF, Dubois LG, Thompson JW, Moseley MA, McCafferty DG. (2011) Staphylococcus aureus Sortase A Contributes to the Trojan Horse Mechanism of Immune Defense Evasion with Its Intrinsic Resistance to Cys184 Oxidation. ACS Biochemistry. 2011 Sept; 50(35):7591-7599. Hwang S, Schmitt AA, Luteran AE, Toone EJ, McCafferty DG. (2011) Thermodynamic Characterization of the Binding Interaction between the Histone Demethylase LSD1/KDM1 and CoREST. ACS Biochemistry. 2011 Feb; 50(4):546-557. Hu X, Hu H, Melvin JA, Clancy KW, McCafferty DG, Yang W. (2011) Autocatalytic Intramolecular Isopeptide Bond Formation in Gram-Positive Bacterial Pili: A QM/MM Simulation. J Am Chem Soc. 2011 Jan; 133(3):478-485. Schmidt JW, Greenough A, Burns MM, Luteran AE, McCafferty DG. (2010) Generation of Ramoplanin-Resistant Staphylococcus aureus. FEMS Microbiology Letters. 2010 Sept; 310(2):103-111. Clancy KW, Melvin JA, McCafferty DG. (2010) Sortase Transpeptidases: Insights Into Mechanism, Substrate Specificity, and Inhibition. Biopolymers (Pept Sci) 94: 385-396, 2010. Hamburger JB, Hoertz AJ, Lee A, Senturia RJ, McCafferty DG, Loll PJ. (2009) A crystal structure of a dimer of the antibiotic ramoplanin illustrates membrane positioning and a potential Lipid II docking interface. Proc. Natl. Acad. Sci. Epub 2009 Aug 3. Gaweska H, Henderson Pozzi M, Schmidt DM, McCafferty DG, Fitzpatrick PF. (2009) Use of pH and kinetic isotope effects to establish chemistry as rate-limiting in oxidation of a peptide substrate by LSD1. Biochemistry. 2009 Jun 16;48(23):5440-5. Deshmukh HS, Hamburger JB, Ahn SH, McCafferty DG, Yang SR, Fowler VG Jr. (2009) The Critical Role of NOD2 in Regulating the Immune Response to Staphylococcus aureus. Infect Immun. 2009 Apr;77(4):1376-82. Race PR, Bentley ML, Melvin JA, Crow A, Hughes RK, Smith WD, Sessions RB, Kehoe MA, McCafferty DG, Banfield MJ. (2009) Crystal structure of S. pyogenes sortase A: Implications for sortase mechanism. J Biol Chem. Epub 2009 Jan 6. Bentley ML, Lamb EC, McCafferty DG. (2008) Mutagenesis Studies of Substrate Recognition and Catalysis in the Sortase A Transpeptidase from Staphylococcus aureus. J Biol Chem. 2008 May 23;283(21):14762-71. Epub 2008 Mar 28. Gooden DM, Schmidt DM, Pollock JA, Babadi AM, McCafferty DM. (2008) Facile synthesis of substituted trans-2-arylcyclopropylamine inhibitors of the human histone demethylase LSD1 and monoamine oxidases A and B. Bioorg Med Chem Lett. May 2008 15;18(10):3047-51. Epub 2008 Jan 8. Frankel BA,Tong Y, Bentley ML, Fitzgerald MC, McCafferty DG. (2007) Mutational Analysis of Active Site Residues in the Staphylococcus aureus Transpeptidase SrtA. Biochemistry. 2007 Jun 19;46(24):7269-78. Epub 2007 May 23. Schmidt DM, McCafferty DG. (2007) trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry. 2007 Apr 10;46(14):4408-16. Epub 2007 Mar 17. Bentley ML, Gaweska H, Kielec JM, McCafferty DG. (2007) Engineering the substrate specificity of staphylococcus aureus sortase A: The beta 6/beta 7 loop from SrtB confers NPQTN recognition to SrtA. J Biol Chem 2007 Mar 2;282(9):6571-81. Epub 2007 Jan 2. Frankel BA,Tong Y, Bentley ML, Fitzgerald MC, McCafferty DG. (2007) Mutational Analysis of Active Site Residues in the Staphylococcus aureus Transpeptidase SrtA. Biochemistry. 2007 Jun 19;46(24):7269-78. Epub 2007 May 23. McCafferty DG. (2006) Crossing a biological velvet rope. ACS Chem Biol 2006 1(6):339-40 Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R. (2006) Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol 2006 13:563-7 Frankel BA, Kruger RG, Robinson DE, Kelleher NL, McCafferty DG. (2005) Staphylococcus aureus sortase transpeptidase SrtA: insight into the kinetic mechanism and evidence for a reverse protonation catalytic mechanism. Biochemistry 2005 44:11188-200 Kruger RG, Barkallah S, Frankel BA, McCafferty DG. (2004) Inhibition of the Staphylococcus aureus sortase transpeptidase SrtA by phosphinic peptidomimetics. Bioorg Med Chem 2004 12:3723-9 Frankel BA, McCafferty DG. (2004) Profiling natural product biosynthesis. Chem Biol 2004 11:290-1 Striplin DR, Reece SY, McCafferty DG, Wall CG, Friesen DA, Erickson BW, Meyer TJ. (2004) Solvent dependence of intramolecular electron transfer in a helical oligoproline assembly. J Am Chem Soc 2004 126:5282-91 Frankel BA, Bentley M, Kruger RG, McCafferty DG. (2004) Vinyl sulfones: inhibitors of SrtA, a transpeptidase required for cell wall protein anchoring and virulence in Staphylococcus aureus. J Am Chem Soc 2004 126:3404-5 Loyola A, He S, Oh S, McCafferty DG, Reinberg D. (2004) Techniques used to study transcription on chromatin templates. Methods Enzymol 2004 377:474-99 Kruger RG, Dostal P, McCafferty DG. (2004) Development of a high-performance liquid chromatography assay and revision of kinetic parameters for the Staphylococcus aureus sortase transpeptidase SrtA. Anal Biochem 326:42-8 Kruger RG, Otvos B, Frankel BA, Bentley M, Dostal P, McCafferty DG. (2004) Analysis of the substrate specificity of the Staphylococcus aureus sortase transpeptidase SrtA.Biochemistry. 2004 43:1541-51 He S, Bauman D, Davis JS, Loyola A, Nishioka K, Gronlund JL, Reinberg D, Meng F, Kelleher N, McCafferty DG. (2003) Facile synthesis of site-specifically acetylated and methylated histone proteins: reagents for evaluation of the histone code hypothesis. Proc Natl Acad Sci U S A 2003 100:12033-8 Kapustin GV, Fejer G, Gronlund JL, McCafferty DG, Seto E, Etzkorn FA. (2003). Phosphorus-based SAHA analogues as histone deacetylase inhibitors. Org Lett 2003 5:3053-6 McCafferty DG, Cudic P, Frankel BA, Barkallah S, Kruger RG, Li W. (2002) Chemistry and biology of the ramoplanin family of peptide antibiotics. Biopolymers 2002 66:261-84 Huang CY, He S, DeGrado WF, McCafferty DG, Gai F. (2002) Light-induced helix formation. J Am Chem Soc 2002 124:12674-5 Kruger RG, Dostal P, McCafferty DG. (2002) An economical and preparative orthogonal solid phase synthesis of fluorescein and rhodamine derivatized peptides: FRET substrates for the Staphylococcus aureus sortase SrtA transpeptidase reaction. Chem Commun (Camb) 2002 2092-3 Cudic P, Behenna DC, Kranz JK, Kruger RG, Wand AJ, Veklich YI, Weisel JW, McCafferty DG. (2002) Functional analysis of the lipoglycodepsipeptide antibiotic ramoplanin. Chem Biol 2002 9:897-906 Cudic P, Kranz JK, Behenna DC, Kruger RG, Tadesse H, Wand AJ, Veklich YI, Weisel JW, McCafferty DG. (2002) Complexation of peptidoglycan intermediates by the lipoglycodepsipeptide antibiotic ramoplanin: minimal structural requirements for intermolecular complexation and fibril formation. Proc Natl Acad Sci U S A 2002. 99:7384-9 Cudic P, Behenna DC, Yu MK, Kruger RG, Szewczuk LM, McCafferty DG. (2001) Synthesis of P(1)-Citronellyl-P(2)-alpha-D-pyranosyl pyrophosphates as potential substrates for the E. coli undecaprenyl-pyrophosphoryl-N-acetylglucoseaminyl transferase MurG. Bioorg Med Chem Lett 2001 11:3107-10 McCafferty DG, Cudic P, Yu MK, Behenna DC, Kruger R. (1999) Synergy and duality in peptide antibiotic mechanisms. Curr Opin Chem Biol 1999 3:672-80 Lessard IA, Pratt SD, McCafferty DG, Bussiere DE, Hutchins C, Wanner BL, Katz L, Walsh CT. (1998) Homologs of the vancomycin resistance D-Ala-D-Ala dipeptidase VanX in Streptomyces toyocaensis, Escherichia coli and Synechocystis: attributes of catalytic efficiency, stereoselectivity and regulation with implications for function. Chem Biol 1998 5:489-504 McCafferty DG, Lessard IA, Walsh CT. (1997) Mutational analysis of potential zinc-binding residues in the active site of the enterococcal D-Ala-D-Ala dipeptidase VanX. Biochemistry. 1997. 36:10498-505 McCafferty DG, Friesen DA, Danielson E, Wall CG, Saderholm MJ, Erickson BW, Meyer TJ. (1996) Photochemical energy conversion in a helical oligoproline assembly. Proc Natl Acad Sci U S A 1996. 93:8200-4