Host-primed Ebola virus GP exposes a hydrophobic NPC1 receptor-binding pocket, revealing a target for broadly neutralizing antibodies

mBio

Volumn 7, Issue 1, 2016, Pages

  Bornholdt, Zachary A ^a   Ndungo, Esther ^b   Fusco, Marnie L ^a   Bale, Shridhar ^a   Flyak, Andrew I ^c   Crowe, James E ^c,d   Chandran, Kartik ^b   Saphire, Erica Ollmann ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^c VANDERBILT UNIVERSITY   (United States)

^d VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOPROTEIN; NEUTRALIZING ANTIBODY; NIEMANN PICK C1; UNCLASSIFIED DRUG; VIRUS PROTEIN; CARRIER PROTEIN; ENVELOPE GLYCOPROTEIN, EBOLA VIRUS; MEMBRANE PROTEIN; NPC1 PROTEIN, HUMAN; PROTEIN BINDING; VIRUS ANTIBODY; VIRUS ENVELOPE PROTEIN; VIRUS RECEPTOR;

ANIMAL CELL; ARTICLE; BINDING SITE; CONTROLLED STUDY; CRYSTAL STRUCTURE; EBOLAVIRUS; FILOVIRUS; HOST CELL; HYDROPHOBICITY; MUTAGENESIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN DEGRADATION; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; RECEPTOR BINDING; VIRUS ENTRY; CELL LINE; CHEMICAL PHENOMENA; CHEMISTRY; GENETICS; HEMORRHAGIC FEVER, EBOLA; HUMAN; IMMUNOLOGY; METABOLISM; MUTATION; PHYSIOLOGY; X RAY CRYSTALLOGRAPHY;

ANTIBODIES, NEUTRALIZING; ANTIBODIES, VIRAL; CARRIER PROTEINS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; EBOLAVIRUS; HEMORRHAGIC FEVER, EBOLA; HUMANS; HYDROPHOBIC AND HYDROPHILIC INTERACTIONS; MEMBRANE GLYCOPROTEINS; MUTAGENESIS; MUTATION; PROTEIN BINDING; RECEPTORS, VIRUS; VIRAL ENVELOPE PROTEINS; VIRUS INTERNALIZATION;

EID: 84960154024     PISSN: 21612129     EISSN: 21507511     Source Type: Journal    
DOI: 10.1128/mBio.02154-15     Document Type: Article

References (49)

1. De la Vega MA, Stein D, Kobinger GP. 2015. Ebolavirus evolution: past and present. PLoS Pathog 11:e1005221. http://dx.doi.org/10.1371/journal.ppat.1005221.
2. Negredo A, Palacios G, Vázquez-Morón S, González F, Dopazo H, Molero F, Juste J, Quetglas J, Savji N, de la Cruz Martínez M, Herrera JE, Pizarro M, Hutchison SK, Echevarría JE, Lipkin WI, Tenorio A. 2011. Discovery of an ebolavirus-like filovirus in Europe. PLoS Pathog 7:e1002304. http://dx.doi.org/10.1371/journal.ppat.1002304.
3. Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N, Soropogui B, Sow MS, Keïta S, De Clerck H, Tiffany A, Dominguez G, Loua M, Traoré A, Kolié M, Malano ER, Heleze E, Bocquin A, Mély S, Raoul H, Caro V, Cadar D, Gabriel M, Pahlmann M, Tappe D, Schmidt-Chanasit J, Impouma B, Diallo AK, Formenty P, Van Herp M, Gunther S. 2014. Emergence of Zaire Ebola virus disease in Guinea. N Engl J Med 371:1418–1425. http://dx.doi.org/10.1056/NEJMoa1404505.
4. Lee JE, Fusco ML, Hessell AJ, Oswald WB, Burton DR, Saphire EO. 2008. Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature 454:177–182. http://dx.doi.org/10.1038/nature07082.
5. Lee JE, Saphire EO. 2009. Neutralizing ebolavirus: structural insights into the envelope glycoprotein and antibodies targeted against it. Curr Opin Struct Biol 19:408–417. http://dx.doi.org/10.1016/j.sbi.2009.05.004.
6. Jeffers SA, Sanders DA, Sanchez A. 2002. Covalent modifications of the Ebola virus glycoprotein. J Virol 76:12463–12472. http://dx.doi.org/10.1128/JVI.76.24.12463-12472.2002.
7. Kaletsky RL, Simmons G, Bates P. 2007. Proteolysis of the Ebola virus glycoproteins enhances virus binding and infectivity. J Virol 81: 13378–13384. http://dx.doi.org/10.1128/JVI.01170-07.
8. Schornberg K, Matsuyama S, Kabsch K, Delos S, Bouton A, White J. 2006. Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J Virol 80:4174–4178. http://dx.doi.org/10.1128/JVI.80.8.4174-4178.2006.
9. Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM. 2005. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308:1643–1645. http://dx.doi.org/10.1126/science.1110656.
10. Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, Ndungo E, Sandesara RG, Carette JE, Kuehne AI, Ruthel G, Pfeffer SR, Dye JM, Whelan SP, Brummelkamp TR, Chandran K. 2012. Ebola virus entry requires the host-programmed recognition of an intracellular receptor. EMBO J 31:1947–1960. http://dx.doi.org/10.1038/emboj.2012.53.
11. Hashiguchi T, Fusco ML, Bornholdt ZA, Lee JE, Flyak AI, Matsuoka R, Kohda D, Yanagi Y, Hammel M, Crowe JE, Jr., Saphire EO. 2015. Structural basis for Marburg virus neutralization by a cross-reactive human antibody. Cell 160:904–912. http://dx.doi.org/10.1016/j.cell.2015.01.041.
12. Mulherkar N, Raaben M, de la Torre JC, Whelan SP, Chandran K. 2011. The Ebola virus glycoprotein mediates entry via a non-classical dynamindependent macropinocytic pathway. Virology 419:72–83. http://dx.doi.org/10.1016/j.virol.2011.08.009.
13. Saeed MF, Kolokoltsov AA, Albrecht T, Davey RA. 2010. Cellular entry of Ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathog 6:e1001110. http://dx.doi.org/10.1371/journal.ppat.1001110.
14. Mingo RM, Simmons JA, Shoemaker CJ, Nelson EA, Schornberg KL, D’Souza RS, Casanova JE, White JM. 2015. Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to NPC1_ endolysosomes is a rate-defining step. J Virol 89:2931–2943. http://dx.doi.org/10.1128/JVI.03398-14.
15. Nanbo A, Imai M, Watanabe S, Noda T, Takahashi K, Neumann G, Halfmann P, Kawaoka Y. 2010. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog 6:e1001121. http://dx.doi.org/10.1371/journal.ppat.1001121.
16. Dube D, Brecher MB, Delos SE, Rose SC, Park EW, Schornberg KL, Kuhn JH, White JM. 2009. The primed ebolavirus glycoprotein (19-kilodalton GP1,2): sequence and residues critical for host cell binding. J Virol 83:2883–2891. http://dx.doi.org/10.1128/JVI.01956-08.
17. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, Kuehne AI, Kranzusch PJ, Griffin AM, Ruthel G, Dal Cin P, Dye JM, Whelan SP, Chandran K, Brummelkamp TR. 2011. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477: 340–343. http://dx.doi.org/10.1038/nature10348.
18. Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J. 2011. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature 477: 344–348. http://dx.doi.org/10.1038/nature10380.
19. Krishnan A, Miller EH, Herbert AS, Ng M, Ndungo E, Whelan SP, Dye JM, Chandran K. 2012. Niemann-Pick C1 (NPC1)/NPC1-like1 chimeras define sequences critical for NPC1’s function as a flovirus entry receptor. Viruses 4:2471–2484. http://dx.doi.org/10.3390/v4112471.
20. Herbert AS, Davidson C, Kuehne AI, Bakken R, Braigen SZ, Gunn KE, Whelan SP, Brummelkamp TR, Twenhafel NA, Chandran K, Walkley SU, Dye JM. 2015. Niemann-Pick C1 is essential for ebolavirus replication and pathogenesis in vivo. mBio 6:e00565-15. http://dx.doi.org/10.1128/mBio.00565-15.
21. Maruyama T, Rodriguez LL, Jahrling PB, Sanchez A, Khan AS, Nichol ST, Peters CJ, Parren PW, Burton DR. 1999. Ebola virus can be effectively neutralized by antibody produced in natural human infection. J Virol 73:6024–6030.
22. Flyak AI, Ilinykh PA, Murin CD, Garron T, Shen X, Fusco ML, Hashiguchi T, Bornholdt ZA, Slaughter JC, Sapparapu G, Klages C, Ksiazek TG, Ward AB, Saphire EO, Bukreyev A, Crowe JE, Jr.. 2015. Mechanism of human antibody-mediated neutralization of Marburg virus. Cell 160:893–903. http://dx.doi.org/10.1016/j.cell.2015.01.031.
23. Bale S, Liu T, Li S, Wang Y, Abelson D, Fusco M, Woods VL, Jr.., Saphire EO. 2011. Ebola virus glycoprotein needs an additional trigger, beyond proteolytic priming for membrane fusion. PLoS Negl Trop. Dis 5:e1395. http://dx.doi.org/10.1371/journal.pntd.0001395.
24. Brindley MA, Hughes L, Ruiz A, McCray PB, Jr.., Sanchez A, Sanders DA, Maury W. 2007. Ebola virus glycoprotein 1: identification of residues important for binding and postbinding events. J Virol 81:7702–7709. http://dx.doi.org/10.1128/JVI.02433-06.
25. Manicassamy B, Wang J, Jiang H, Rong L. 2005. Comprehensive analysis of Ebola virus GP1 in viral entry. J Virol 79:4793–4805. http://dx.doi.org/10.1128/JVI.79.8.4793-4805.2005.
26. Mpanju OM, Towner JS, Dover JE, Nichol ST, Wilson CA. 2006. Identification of two amino acid residues on Ebola virus glycoprotein 1 critical for cell entry. Virus Res 121:205–214. http://dx.doi.org/10.1016/j.virusres.2006.06.002.
27. Martinez O, Ndungo E, Tantral L, Miller EH, Leung LW, Chandran K, Basler CF. 2013. A mutation in the Ebola virus envelope glycoprotein restricts viral entry in a host species-and cell-type-specific manner. J Virol 87:3324–3334. http://dx.doi.org/10.1128/JVI.01598-12.
28. Miller EH, Harrison JS, Radoshitzky SR, Higgins CD, Chi X, Dong L, Kuhn JH, Bavari S, Lai JR, Chandran K. 2011. Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. J Biol Chem 286: 15854–15861. http://dx.doi.org/10.1074/jbc.M110.207084.
29. Miller EH, Chandran K. 2012. Filovirus entry into cells—new insights. Curr Opin Virol 2:206–214. http://dx.doi.org/10.1016/j.coviro.2012.02.015.
30. Dias JM, Kuehne AI, Abelson DM, Bale S, Wong AC, Halfmann P, Muhammad MA, Fusco ML, Zak SE, Kang E, Kawaoka Y, Chandran K, Dye JM, Saphire EO. 2011. A shared structural solution for neutralizing ebolaviruses. Nat Struct Mol Biol 18:1424–1427. http://dx.doi.org/10.1038/nsmb.2150.
31. Murin CD, Fusco ML, Bornholdt ZA, Qiu X, Olinger GG, Zeitlin L, Kobinger GP, Ward AB, Saphire EO. 2014. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proc Natl Acad SciU S A 111:17182–17187. http://dx.doi.org/10.1073/pnas.1414164111.
32. Ng M, Ndungo E, Jangra RK, Cai Y, Postnikova E, Radoshitzky SR, Dye JM, Ramírez de Arellano E, Negredo A, Palacios G, Kuhn JH, Chandran K. 2014. Cell entry by a novel European filovirus requires host endosomal cysteine proteases and Niemann-Pick C1. Virology 468–470:637–646. http://dx.doi.org/10.1016/j.virol.2014.08.019.
33. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, Fausther-Bovendo H, Wei H, Aviles J, Hiatt E, Johnson A, Morton J, Swope K, Bohorov O, Bohorova N, Goodman C, Kim D, Pauly MH, Velasco J, Pettitt J, Olinger GG, Whaley K, Xu B, Strong JE, Zeitlin L, Kobinger GP. 2014. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 514:47–53. http://dx.doi.org/10.1038/nature13777.
34. Carroll MW, Matthews DA, Hiscox JA, Elmore MJ, Pollakis G, Rambaut A, Hewson R, García-Dorival I, Bore JA, Koundouno R, Abdellati S, Afrough B, Aiyepada J, Akhilomen P, Asogun D, Atkinson B, Badusche M, Bah A, Bate S, Baumann J, Becker D, Becker-Ziaja B, Bocquin A, Borremans B, Bosworth A, Boettcher JP, Cannas A, Carletti F, Castilletti C, Clark S, Colavita F, Diederich S, Donatus A, Duraffour S, Ehichioya D, Ellerbrok H, Fernandez-Garcia MD, Fizet A, Fleischmann E, Gryseels S, Hermelink A, Hinzmann J, Hopf-Guevara U, Ighodalo Y, Jameson L, Kelterbaum A, Kis Z, Kloth S, Kohl C, Korva M. 2015. Temporal and spatial analysis of the 2014–2015 Ebola virus outbreak in West Africa. Nature 524:97–101. http://dx.doi.org/10.1038/nature14594.
35. Maganga GD, Kapetshi J, Berthet N, Kebela Ilunga B, Kabange F, Mbala Kingebeni P, Mondonge V, Muyembe JJ, Bertherat E, Briand S, Cabore J, Epelboin A, Formenty P, Kobinger G, González-Angulo L, Labouba I, Manuguerra JC, Okwo-Bele JM, Dye C, Leroy EM. 2014. Ebola virus disease in the Democratic Republic of the Congo. N Engl J Med 371:2083–2091. http://dx.doi.org/10.1056/NEJMoa1411099.
36. Towner JS, Sealy TK, Khristova ML, Albariño CG, Conlan S, Reeder SA, Quan PL, Lipkin WI, Downing R, Tappero JW, Okware S, Lutwama J, Bakamutumaho B, Kayiwa J, Comer JA, Rollin PE, Ksiazek TG, Nichol ST. 2008. Newly discovered Ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathog 4:e1000212. http://dx.doi.org/10.1371/journal.ppat.1000212.
37. Shoemaker T, MacNeil A, Balinandi S, Campbell S, Wamala JF, Mc-Mullan LK, Downing R, Lutwama J, Mbidde E, Ströher U, Rollin PE, Nichol ST. 2012. Reemerging Sudan Ebola virus disease in Uganda, 2011. Emerg Infect Dis 18:1480–1483. http://dx.doi.org/10.3201/eid1809.111536.
38. Mylne A, Brady OJ, Huang Z, Pigott DM, Golding N, Kraemer MU, Hay SI. 2014. A comprehensive database of the geographic spread of past human Ebola outbreaks. Sci Data 1:140042. http://dx.doi.org/10.1038/sdata.2014.42.
39. McCoy AJ, Grosse-Kunstleve RW, Adams PD, Winn MD, Storoni LC, Read RJ. 2007. Phaser crystallographic software. J Appl Crystallogr 40: 658–674. http://dx.doi.org/10.1107/S0021889807021206.
40. Collaborative Computational Project Number 4. 1994. The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50:760–763. http://dx.doi.org/10.1107/S0907444994003112.
41. Emsley P, Cowtan K. 2004. Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60:2126–2132. http://dx.doi.org/10.1107/S0907444904019158.
42. Evans P. 2006. Scaling and assessment of data quality. Acta Crystallogr DBiol Crystal logr 62:72–82. http://dx.doi.org/10.1107/S0907444905036693.
43. Adams PD, Afonine PV, Bunkóczi G, Chen VB, Davis IW, Echols N, Headd JJ, Hung LW, Kapral GJ, Grosse-Kunstleve RW, McCoy AJ, Moriarty NW, Oeffner R, Read RJ, Richardson DC, Richardson JS, Terwilliger TC, Zwart PH. 2010. PHENIX: a comprehensive pythonbased system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66:213–221. http://dx.doi.org/10.1107/S0907444909052925.
44. Painter J, Merritt EA. 2006. Optimal description of a protein structure in terms of multiple groups undergoing TLS motion. Acta CrystallogrDBiol Crystallogr 62:439–450. http://dx.doi.org/10.1107/S0907444906005270.
45. Painter J, Merritt EA. 2006. TLSMD web server for the generation of multi-group TLS models. J Appl Crystallogr 39:109–111. http://dx.doi.org/10.1107/S0021889805038987.
46. Brünger AT. 1992. Free R-value—a novel statistical quantity for assessing the accuracy of crystal-structures. Nature 355:472–475. http://dx.doi.org/10.1038/355472a0.
47. Chen VB, Arendall WB, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, Murray LW, Richardson JS, Richardson DC. 2010. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr 66:12–21. http://dx.doi.org/10.1107/S0907444909042073.
48. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA. 2001. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci U S A 98:10037–10041. http://dx.doi.org/10.1073/pnas.181342398.
49. Takada A, Robison C, Goto H, Sanchez A, Murti KG, Whitt MA, Kawaoka Y. 1997. A system for functional analysis of Ebola virus glycoprotein. Proc Natl Acad Sci U S A 94(26):14764–14769.