A single-domain llama antibody potently inhibits the enzymatic activity of botulinum neurotoxin by binding to the non-catalytic α-exosite binding region

Journal of Molecular Biology

Volumn 397, Issue 4, 2010, Pages 1106-1118

  Dong, Jianbo ^a   Thompson, Aaron A ^b   Fan, Yongfeng ^a   Lou, Jianlong ^a   Conrad, Fraser ^a   Ho, Mengfei ^c   Pires Alves, Melissa ^c   Wilson, Brenda A ^c   Stevens, Raymond C ^b   Marks, James D ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

^c UNIVERSITY OF ILLINOIS AT URBANA CHAMPAIGN   (United States)

Author keywords

Botulinum neurotoxin type A; Llama VHH; Na ve yeast displayed library; Single domain antibody; exosite

Indexed keywords

ANTIBODY; BOTULINUM TOXIN A; LLAMA ANTIBODY; SYNAPTOSOMAL ASSOCIATED PROTEIN 25; UNCLASSIFIED DRUG;

ARTICLE; BINDING SITE; CATALYSIS; COMPLEX FORMATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; DISSOCIATION CONSTANT; ENZYME INHIBITION; ENZYME SUBSTRATE COMPLEX; FLOW CYTOMETRY; HEAT TREATMENT; HEAVY CHAIN; IC 50; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CLEAVAGE; PROTEIN DENATURATION; PROTEIN DOMAIN; SACCHAROMYCES CEREVISIAE;

CAMELIDAE; LAMA (MAMMAL); SACCHAROMYCES CEREVISIAE;

EID: 77950022629     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jmb.2010.01.070     Document Type: Article

References (70)

1. Arnon S.A., Schecter R., Inglesby T.V., Henderson D.A., Bartlett J.G., Ascher M.S., et al. Botulinum toxin as a biological weapon. JAMA 2001, 285:1059-1070.
2. Control C.F.D. Botulism in the United States, 1899-1998. Handbook for Epidemiologists, Clinicians, and Laboratory Workers 1998, U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA, downloadable at http://www.bt.cdc.gov/agent/botulism/index,asp.
3. Gill M.D. Bacterial toxins: a table of lethal amounts. Microbiol. Rev. 1982, 46:86-94.
4. Lacy D.B., Tepp W., Cohen A.C., DasGupta B.R., Stevens R.C. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat. Struct. Biol. 1998, 5:898-902.
5. Montecucco C., Schiavo G. Structure and function of tetanus and botulinum neurotoxins. Q. Rev. Biophys. 1995, 28:423-472.
6. Simpson L.L. Kinetic studies on the interaction between botulinum toxin type A and the chloinergic neuromuscular junction. J. Pharmacol. Exp. Ther. 1980, 212:16-21.
7. Dolly J.O., Black J., Williams R.S., Melling J. Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature 1984, 307:457-460.
8. Dong M., Yeh F., Tepp W.H., Dean C., Johnson E.A., Janz R., Chapman E.R. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006, 312:592-596.
9. Mahrhold S., Rummel A., Bigalke H., Davletov B., Binz T. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett. 2006, 580:2011-2014.
10. Fischer A., Montal M. Single molecule detection of intermediates during botulinum neurotoxin translocation across membranes. Proc. Natl Acad. Sci. USA 2007, 104:10447-10452.
11. Schiavo G., Benfenati F., B., P., Rossetto O., Polverino D.L., P., DasGupta B.R., Montecucco C. Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 1992, 359:832-835.
12. Schiavo G., Rossetto O., Catsicas S., Polverino D.L., P., DasGupta B.R., Benfenati F., Montecucco C. Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E. J. Biol. Chem. 1993, 268:23784-23787.
13. Franz D.R., Pitt L.M., Clayton M.A., Hanes M.A., Rose K.J. Efficacy of prophylactic and therapeutic administration of antitoxin for inhalation botulism. Botulinum and Tetanus Neurotoxins: Neurotransmission and Biomedical Aspects 1993, 473-476. Plenum Press, New York, NY. B.R. DasGupta (Ed.).
14. Black R.E., Gunn R.A. Hypersensitivity reactions associated with botulinal antitoxin. Am. J. Med. 1980, 69:567-570.
15. Hibbs R.G., Weber J.T., Corwin A., Allos B.M., Abd el Rehim M.S., Sharkawy S.E., et al. Experience with the use of an investigational F(ab′)2 heptavalent botulism immune globulin of equine origin during an outbreak of type E origin in Egypt. Clin. Infect. Dis. 1996, 23:337-340.
16. Arnon S.S., Schechter R., Maslanka S.E., Jewell N.P., Hatheway C.L. Human botulism immune globulin for the treatment of infant botulism. N. Engl. J. Med. 2006, 354:462-471.
17. Ravichandran E., Gong Y., Al Saleem F.H., Ancharski D.M., Joshi S.G., Simpson L.L. An initial assessment of the systemic pharmacokinetics of botulinum toxin. J. Pharmacol. Exp. Ther. 2006, 318:1343-1351.
18. Hall Y.H., Chaddock J.A., Moulsdale H.J., Kirby E.R., Alexander F.C., Marks J.D., Foster K.A. Novel application of an in vitro technique to the detection and quantification of botulinum neurotoxin antibodies. J. Immunol. Methods 2004, 288:55-60.
19. Takahashi T., Joshi S.G., Al-Saleem F., Ancharski D., Singh A., Nasser Z., Simpson L.L. Localization of the sites and characterization of the mechanisms by which anti-light chain antibodies neutralize the actions of the botulinum holotoxin. Vaccine 2009, 27:2616-2624.
20. Chai Q., Arndt J.W., Dong M., Tepp W.H., Johnson E.A., Chapman E.R., Stevens R.C. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 2006, 444:1096-1100.
21. Jin R., Rummel A., Binz T., Brunger A.T. Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature 2006, 444:1092-1095.
22. Stenmark P., Dupuy J., Imamura A., Kiso M., Stevens R.C. Crystal structure of botulinum neurotoxin type A in complex with the cell surface co-receptor GT1b-insight into the toxin-neuron interaction. PLoS Pathog. 2008, 4:e1000129.
23. Dickerson T.J., Janda K.D. The use of small molecules to investigate molecular mechanisms and therapeutic targets for treatment of botulinum neurotoxin A intoxication. ACS Chem. Biol. 2006, 1:359-369.
24. Fischer A., Nakai Y., Eubanks L.M., Clancy C.M., Tepp W.H., Pellett S., et al. Bimodal modulation of the botulinum neurotoxin protein-conducting channel. Proc. Natl Acad. Sci. USA 2009, 106:1330-1335.
25. Burnett J.C., Ruthel G., Stegmann C.M., Panchal R.G., Nguyen T.L., Hermone A.R., et al. Inhibition of metalloprotease botulinum serotype A from a pseudo-peptide binding mode to a small molecule that is active in primary neurons. J. Biol. Chem. 2007, 282:5004-5014.
26. Park J.G., Sill P.C., Makiyi E.F., Garcia-Sosa A.T., Millard C.B., Schmidt J.J., Pang Y.P. Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A. Bioorg. Med. Chem. 2006, 14:395-408.
27. Breidenbach M.A., Brunger A.T. Substrate recognition strategy for botulinum neurotoxin serotype A. Nature 2004, 432:925-929.
28. Muller J., Isermann B., Ducker C., Salehi M., Meyer M., Friedrich M., et al. An exosite-specific ssDNA aptamer inhibits the anticoagulant functions of activated protein C and enhances inhibition by protein C inhibitor. Chem. Biol. 2009, 16:442-451.
29. Wu Y., Eigenbrot C., Liang W.C., Stawicki S., Shia S., Fan B., et al. Structural insight into distinct mechanisms of protease inhibition by antibodies. Proc. Natl Acad. Sci. USA 2007, 104:19784-19789.
30. De Genst E., Silence K., Decanniere K., Conrath K., Loris R., Kinne J., et al. Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. Proc. Natl Acad. Sci. USA 2006, 103:4586-4591.
31. Ratier L., Urrutia M., Paris G., Zarebski L., Frasch A.C., Goldbaum F.A. Relevance of the diversity among members of the Trypanosoma cruzi trans-sialidase family analyzed with camelids single-domain antibodies. PLoS ONE 2008, 3:e3524.
32. Pires-Alves M., Ho M., Aberle K.K., Janda K.D., Wilson B.A. Tandem fluorescent proteins as enhanced FRET-based substrates for botulinum neurotoxin activity. Toxicon 2009, 53:392-399.
33. Krissinel E., Henrick K. Inference of macromolecular assemblies from crystalline state. J. Mol. Biol. 2007, 372:774-797.
34. Shindyalov I.N., Bourne P.E. Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. Protein Eng. 1998, 11:739-747.
35. Rossetto O., Schiavo G., Montecucco C., Poulain B., Deloye F., Lozzi L., Shone C.C. SNARE motif and neurotoxins. Nature 1994, 372:415-416.
36. Washbourne P., Pellizzari R., Baldini G., Wilson M.C., Montecucco C. Botulinum neurotoxin types A and E require the SNARE motif in SNAP-25 for proteolysis. FEBS Lett. 1997, 418:1-5.
37. Marks J.D., Hoogenboom H.R., Bonnert T.P., McCafferty J., Griffiths A.D., Winter G. By-passing immunization: human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 1991, 222:581-597.
38. Feldhaus M.J., Siegel R.W., Opresko L.K., Coleman J.R., Feldhaus J.M., Yeung Y.A., et al. Flow-cytometric isolation of human antibodies from a nonimmune Saccharomyces cerevisiae surface display library. Nat. Biotechnol. 2003, 21:163-170.
39. Amersdorfer P., Wong C., Smith T., Chen S., Deshpande S., Sheridan R., Marks J.D. Genetic and immunological comparison of anti-botulinum type A antibodies from immune and non-immune human phage libraries. Vaccine 2002, 20:1640-1648.
40. Wesolowski J., Alzogaray V., Reyelt J., Unger M., Juarez K., Urrutia M., et al. Single domain antibodies: promising experimental and therapeutic tools in infection and immunity. Med. Microbiol. Immunol. 2009, 198:157-174.
41. Monegal A., Ami D., Martinelli C., Huang H., Aliprandi M., Capasso P., et al. Immunological applications of single-domain llama recombinant antibodies isolated from a naive library. Protein Eng. Des. Sel. 2009, 22:273-280.
42. Razai A., Garcia-Rodriguez C., Lou J., Geren I.N., Forsyth C.M., Robles Y., et al. Molecular evolution of antibody affinity for sensitive detection of botulinum neurotoxin type A. J. Mol. Biol. 2005, 351:158-169.
43. Perelson A.S., Oster G.F. Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self non-self discrimination. J. Theor. Biol. 1979, 81:645-670.
44. Sheets M.D., Amersdorfer P., Finnern R., Sargent P., Lindquist E., Schier R., et al. Efficient construction of a large nonimmune phage antibody library: the production of high-affinity human single-chain antibodies to protein antigens. Proc. Natl Acad. Sci. USA 1998, 95:6157-6162.
45. Vaughan T.J., Williams A.J., Pritchard K., Osbourn J.K., Pope A.R., Earnshaw J.C., et al. Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nat. Biotechnol. 1996, 14:309-314.
46. Bowley D.R., Labrijn A.F., Zwick M.B., Burton D.R. Antigen selection from an HIV-1 immune antibody library displayed on yeast yields many novel antibodies compared to selection from the same library displayed on phage. Protein Eng. Des. Sel. 2007, 20:81-90.
47. Wells J.A., de Vos A.M. Hematopoietic receptor complexes. Annu. Rev. Biochem. 1996, 65:609-634.
48. DeLano W.L., Ultsch M.H., de Vos A.M., Wells J.A. Convergent solutions to binding at a protein-protein interface. Science 2000, 287:1279-1283.
49. Cunningham B.C., Wells J.A. Rational design of receptor-specific variants of human growth hormone. Proc. Natl Acad. Sci. USA 1991, 88:3407-3411.
50. Kay B.K., Kurakin A., Hyde-DeRuyscher R. From peptides to drugs via phage display. Drug Discov. Today 1998, 3:370-378.
51. Xu X., Chen Z., Wang Y., Bonewald L., Steffensen B. Inhibition of MMP-2 gelatinolysis by targeting exodomain-substrate interactions. Biochem. J. 2007, 406:147-155.
52. Roberge M., Santell L., Dennis M.S., Eigenbrot C., Dwyer M.A., Lazarus R.A. A novel exosite on coagulation factor VIIa and its molecular interactions with a new class of peptide inhibitors. Biochemistry 2001, 40:9522-9531.
53. Mikkelsen J.H., Gyrup C., Kristensen P., Overgaard M.T., Poulsen C.B., Laursen L.S., Oxvig C. Inhibition of the proteolytic activity of pregnancy-associated plasma protein-A by targeting substrate exosite binding. J. Biol. Chem. 2008, 283:16772-16780.
54. Sperandio O., Miteva M.A., Segers K., Nicolaes G.A., Villoutreix B.O. Screening outside the catalytic site: inhibition of macromolecular inter-actions through structure-based virtual ligand screening experiments. Open Biochem. J. 2008, 2:29-37.
55. Clackson T., Wells J.A. A hot spot of binding energy in a hormone-receptor interface. Science 1995, 267:383-386.
56. Moreira I.S., Fernandes P.A., Ramos M.J. Hot spots-a review of the protein-protein interface determinant amino-acid residues. Proteins 2007, 68:803-812.
57. Braisted A.C., Oslob J.D., Delano W.L., Hyde J., McDowell R.S., Waal N., et al. Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J. Am. Chem. Soc. 2003, 125:3714-3715.
58. Thanos C.D., DeLano W.L., Wells J.A. Hot-spot mimicry of a cytokine receptor by a small molecule. Proc. Natl Acad. Sci. USA 2006, 103:15422-15427.
59. Nowakowski A., Wang C., Powers D.B., Amersdorfer P., Smith T.J., Montgomery V.A., et al. Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody. Proc. Natl Acad. Sci. USA 2002, 99:11346-11350.
60. Levy R., Forsyth C.M., LaPorte S.L., Geren I.N., Smith L.A., Marks J.D. Fine and domain-level epitope mapping of botulinum neurotoxin type A neutralizing antibodies by yeast surface display. J. Mol. Biol. 2007, 365:196-210.
61. Chen S., Barbieri J.T. Unique substrate recognition by botulinum neurotoxins serotypes A and E. J. Biol. Chem. 2006, 281:10906-10911.
62. Gietz R.D., Schiestl R.H. Large-scale high-efficiency yeast transformation using the LiAc/SS carrier DNA/PEG method. Nat. Protoc. 2007, 2:38-41.
63. Schier R., Marks J.D., Wolf E.J., Apell G., Wong C., McCartney J.E., et al. In vitro and in vivo characterization of a human anti-c-erbB-2 single-chain Fv isolated from a filamentous phage antibody library. Immunotechnology 1995, 1:73-81.
64. Garcia-Rodriguez C., Levy R., Arndt J.W., Forsyth C.M., Razai A., Lou J., et al. Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin. Nat. Biotechnol. 2007, 25:107-116.
65. Drake A.W., Myszka D.G., Klakamp S.L. Characterizing high-affinity antigen/antibody complexes by kinetic- and equilibrium-based methods. Anal. Biochem. 2004, 328:35-43.
66. Vaidyanathan V.V., Yoshino K., Jahnz M., Dorries C., Bade S., Nauenburg S., et al. Proteolysis of SNAP-25 isoforms by botulinum neurotoxin types A, C, and E: domains and amino acid residues controlling the formation of enzyme-substrate complexes and cleavage. J. Neurochem. 1999, 72:327-337.
67. Otwinowski Z., Minor W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 1997, 276:307-326.
68. McCoy A.J., Grosse-Kunstleve R.W., Adams P.D., Winn M.D., Storoni L.C., Read R.J. Phaser crystallographic software. J. Appl. Crystallogr. 2007, 40:658-674.
69. Brunger A.T., Adams P.D., Clore G.M., DeLano W.L., Gros P., Grosse-Kunstleve R.W., et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1998, 54:905-921.
70. Emsley P., Cowtan K. Coot: model-building tools for molecular graphics. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60:2126-2132.