Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer
10.1073/pnas.1307382110
Crossref journal-article
Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences (341)
Abstract

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, a membrane-fusing machine, mediates virus entry into host cells and is the sole virus-specific target for neutralizing antibodies. Binding the receptors, CD4 and CCR5/CXCR4, triggers Env conformational changes from the metastable unliganded state to the fusion-active state. We used cryo-electron microscopy to obtain a 6-Å structure of the membrane-bound, heavily glycosylated HIV-1 Env trimer in its uncleaved and unliganded state. The spatial organization of secondary structure elements reveals that the unliganded conformations of both glycoprotein (gp)120 and gp41 subunits differ from those induced by receptor binding. The gp120 trimer association domains, which contribute to interprotomer contacts in the unliganded Env trimer, undergo rearrangement upon CD4 binding. In the unliganded Env, intersubunit interactions maintain the gp41 ectodomain helical bundles in a “spring-loaded” conformation distinct from the extended helical coils of the fusion-active state. Quaternary structure regulates the virus-neutralizing potency of antibodies targeting the conserved CD4-binding site on gp120. The Env trimer architecture provides mechanistic insights into the metastability of the unliganded state, receptor-induced conformational changes, and quaternary structure-based strategies for immune evasion.

Bibliography

Mao, Y., Wang, L., Gu, C., Herschhorn, A., Désormeaux, A., Finzi, A., Xiang, S.-H., & Sodroski, J. G. (2013). Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer. Proceedings of the National Academy of Sciences, 110(30), 12438–12443.

Authors 8
  1. Youdong Mao (first)
  2. Liping Wang (additional)
  3. Christopher Gu (additional)
  4. Alon Herschhorn (additional)
  5. Anik Désormeaux (additional)
  6. Andrés Finzi (additional)
  7. Shi-Hua Xiang (additional)
  8. Joseph G. Sodroski (additional)
References 52 Referenced 96
  1. F Barré-Sinoussi, et al., Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983). (10.1126/science.6189183) / Science / Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS) by Barré-Sinoussi F (1983)
  2. RC Gallo, et al., Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224, 500–503 (1984). (10.1126/science.6200936) / Science / Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS by Gallo RC (1984)
  3. JS Allan, et al., Major glycoprotein antigens that induce antibodies in AIDS patients are encoded by HTLV-III. Science 228, 1091–1094 (1985). (10.1126/science.2986290) / Science / Major glycoprotein antigens that induce antibodies in AIDS patients are encoded by HTLV-III by Allan JS (1985)
  4. WG Robey, et al., Characterization of envelope and core structural gene products of HTLV-III with sera from AIDS patients. Science 228, 593–595 (1985). (10.1126/science.2984774) / Science / Characterization of envelope and core structural gene products of HTLV-III with sera from AIDS patients by Robey WG (1985)
  5. R Wyatt, J Sodroski, The HIV-1 envelope glycoproteins: Fusogens, antigens, and immunogens. Science 280, 1884–1888 (1998). (10.1126/science.280.5371.1884) / Science / The HIV-1 envelope glycoproteins: Fusogens, antigens, and immunogens by Wyatt R (1998)
  6. C Fennie, LA Lasky, Model for intracellular folding of the human immunodeficiency virus type 1 gp120. J Virol 63, 639–646 (1989). (10.1128/jvi.63.2.639-646.1989) / J Virol / Model for intracellular folding of the human immunodeficiency virus type 1 gp120 by Fennie C (1989)
  7. M Moulard, E Decroly, Maturation of HIV envelope glycoprotein precursors by cellular endoproteases. Biochim Biophys Acta 1469, 121–132 (2000). (10.1016/S0304-4157(00)00014-9) / Biochim Biophys Acta / Maturation of HIV envelope glycoprotein precursors by cellular endoproteases by Moulard M (2000)
  8. RA Furuta, CT Wild, Y Weng, CD Weiss, Capture of an early fusion-active conformation of HIV-1 gp41. Nat Struct Biol 5, 276–279 (1998). (10.1038/nsb0498-276) / Nat Struct Biol / Capture of an early fusion-active conformation of HIV-1 gp41 by Furuta RA (1998)
  9. T Koshiba, DC Chan, The prefusogenic intermediate of HIV-1 gp41 contains exposed C-peptide regions. J Biol Chem 278, 7573–7579 (2003). (10.1074/jbc.M211154200) / J Biol Chem / The prefusogenic intermediate of HIV-1 gp41 contains exposed C-peptide regions by Koshiba T (2003)
  10. Y He, et al., Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites. J Virol 77, 1666–1671 (2003). (10.1128/JVI.77.3.1666-1671.2003) / J Virol / Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites by He Y (2003)
  11. Z Si, et al., Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proc Natl Acad Sci USA 101, 5036–5041 (2004). (10.1073/pnas.0307953101) / Proc Natl Acad Sci USA / Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins by Si Z (2004)
  12. DC Chan, D Fass, JM Berger, PS Kim, Core structure of gp41 from the HIV envelope glycoprotein. Cell 89, 263–273 (1997). (10.1016/S0092-8674(00)80205-6) / Cell / Core structure of gp41 from the HIV envelope glycoprotein by Chan DC (1997)
  13. W Weissenhorn, A Dessen, SC Harrison, JJ Skehel, DC Wiley, Atomic structure of the ectodomain from HIV-1 gp41. Nature 387, 426–430 (1997). (10.1038/387426a0) / Nature / Atomic structure of the ectodomain from HIV-1 gp41 by Weissenhorn W (1997)
  14. GB Melikyan, et al., Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion. J Cell Biol 151, 413–423 (2000). (10.1083/jcb.151.2.413) / J Cell Biol / Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion by Melikyan GB (2000)
  15. YD Kwon, et al., Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops. Proc Natl Acad Sci USA 109, 5663–5668 (2012). (10.1073/pnas.1112391109) / Proc Natl Acad Sci USA / Unliganded HIV-1 gp120 core structures assume the CD4-bound conformation with regulation by quaternary interactions and variable loops by Kwon YD (2012)
  16. PD Kwong, et al., Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659 (1998). (10.1038/31405) / Nature / Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody by Kwong PD (1998)
  17. M Pancera, et al., Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proc Natl Acad Sci USA 107, 1166–1171 (2010). (10.1073/pnas.0911004107) / Proc Natl Acad Sci USA / Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility by Pancera M (2010)
  18. V Buzon, et al., Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions. PLoS Pathog 6, e1000880 (2010). (10.1371/journal.ppat.1000880) / PLoS Pathog / Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions by Buzon V (2010)
  19. K Tan, J Liu, J Wang, S Shen, M Lu, Atomic structure of a thermostable subdomain of HIV-1 gp41. Proc Natl Acad Sci USA 94, 12303–12308 (1997). (10.1073/pnas.94.23.12303) / Proc Natl Acad Sci USA / Atomic structure of a thermostable subdomain of HIV-1 gp41 by Tan K (1997)
  20. J Liu, A Bartesaghi, MJ Borgnia, G Sapiro, S Subramaniam, Molecular architecture of native HIV-1 gp120 trimers. Nature 455, 109–113 (2008). (10.1038/nature07159) / Nature / Molecular architecture of native HIV-1 gp120 trimers by Liu J (2008)
  21. TA White, et al., Molecular architectures of trimeric SIV and HIV-1 envelope glycoproteins on intact viruses: Strain-dependent variation in quaternary structure. PLoS Pathog 6, e1001249 (2010). (10.1371/journal.ppat.1001249) / PLoS Pathog / Molecular architectures of trimeric SIV and HIV-1 envelope glycoproteins on intact viruses: Strain-dependent variation in quaternary structure by White TA (2010)
  22. SR Wu, et al., Single-particle cryoelectron microscopy analysis reveals the HIV-1 spike as a tripod structure. Proc Natl Acad Sci USA 107, 18844–18849 (2010). (10.1073/pnas.1007227107) / Proc Natl Acad Sci USA / Single-particle cryoelectron microscopy analysis reveals the HIV-1 spike as a tripod structure by Wu SR (2010)
  23. G Hu, J Liu, KA Taylor, KH Roux, Structural comparison of HIV-1 envelope spikes with and without the V1/V2 loop. J Virol 85, 2741–2750 (2011). (10.1128/JVI.01612-10) / J Virol / Structural comparison of HIV-1 envelope spikes with and without the V1/V2 loop by Hu G (2011)
  24. Y Mao, et al., Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Nat Struct Mol Biol 19, 893–899 (2012). (10.1038/nsmb.2351) / Nat Struct Mol Biol / Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer by Mao Y (2012)
  25. A Finzi, et al., Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitions. Mol Cell 37, 656–667 (2010). (10.1016/j.molcel.2010.02.012) / Mol Cell / Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitions by Finzi A (2010)
  26. DG Myszka, et al., Energetics of the HIV gp120-CD4 binding reaction. Proc Natl Acad Sci USA 97, 9026–9031 (2000). (10.1073/pnas.97.16.9026) / Proc Natl Acad Sci USA / Energetics of the HIV gp120-CD4 binding reaction by Myszka DG (2000)
  27. QJ Sattentau, JP Moore, Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding. J Exp Med 174, 407–415 (1991). (10.1084/jem.174.2.407) / J Exp Med / Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding by Sattentau QJ (1991)
  28. A Désormeaux, et al., The highly conserved layer-3 component of the HIV-1 gp120 inner domain is critical for CD4-required conformational transitions. J Virol 87, 2549–2562 (2013). (10.1128/JVI.03104-12) / J Virol / The highly conserved layer-3 component of the HIV-1 gp120 inner domain is critical for CD4-required conformational transitions by Désormeaux A (2013)
  29. L Chen, et al., Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120. Science 326, 1123–1127 (2009). (10.1126/science.1175868) / Science / Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120 by Chen L (2009)
  30. T Zhou, et al., Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732–737 (2007). (10.1038/nature05580) / Nature / Structural definition of a conserved neutralization epitope on HIV-1 gp120 by Zhou T (2007)
  31. T Zhou, et al., Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811–817 (2010). (10.1126/science.1192819) / Science / Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01 by Zhou T (2010)
  32. B Chen, et al., Structure of an unliganded simian immunodeficiency virus gp120 core. Nature 433, 834–841 (2005). (10.1038/nature03327) / Nature / Structure of an unliganded simian immunodeficiency virus gp120 core by Chen B (2005)
  33. CC Huang, et al., Structure of a V3-containing HIV-1 gp120 core. Science 310, 1025–1028 (2005). (10.1126/science.1118398) / Science / Structure of a V3-containing HIV-1 gp120 core by Huang CC (2005)
  34. M Guttman, M Kahn, NK Garcia, SL Hu, KK Lee, Solution structure, conformational dynamics, and CD4-induced activation in full-length, glycosylated, monomeric HIV gp120. J Virol 86, 8750–8764 (2012). (10.1128/JVI.07224-11) / J Virol / Solution structure, conformational dynamics, and CD4-induced activation in full-length, glycosylated, monomeric HIV gp120 by Guttman M (2012)
  35. N Sullivan, M Thali, C Furman, DD Ho, J Sodroski, Effect of amino acid changes in the V1/V2 region of the human immunodeficiency virus type 1 gp120 glycoprotein on subunit association, syncytium formation, and recognition by a neutralizing antibody. J Virol 67, 3674–3679 (1993). (10.1128/jvi.67.6.3674-3679.1993) / J Virol / Effect of amino acid changes in the V1/V2 region of the human immunodeficiency virus type 1 gp120 glycoprotein on subunit association, syncytium formation, and recognition by a neutralizing antibody by Sullivan N (1993)
  36. SH Xiang, et al., A V3 loop-dependent gp120 element disrupted by CD4 binding stabilizes the human immunodeficiency virus envelope glycoprotein trimer. J Virol 84, 3147–3161 (2010). (10.1128/JVI.02587-09) / J Virol / A V3 loop-dependent gp120 element disrupted by CD4 binding stabilizes the human immunodeficiency virus envelope glycoprotein trimer by Xiang SH (2010)
  37. LM Walker, et al., Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science; Protocol G Principal Investigators 326, 285–289 (2009). (10.1126/science.1178746) / Science / Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target by Walker LM (2009)
  38. JS McLellan, et al., Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480, 336–343 (2011). (10.1038/nature10696) / Nature / Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9 by McLellan JS (2011)
  39. AS Dimitrov, JM Louis, CA Bewley, GM Clore, R Blumenthal, Conformational changes in HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion and inactivation. Biochemistry 44, 12471–12479 (2005). (10.1021/bi051092d) / Biochemistry / Conformational changes in HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion and inactivation by Dimitrov AS (2005)
  40. CC Mische, et al., An alternative conformation of the gp41 heptad repeat 1 region coiled coil exists in the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor. Virology 338, 133–143 (2005). (10.1016/j.virol.2005.05.001) / Virology / An alternative conformation of the gp41 heptad repeat 1 region coiled coil exists in the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor by Mische CC (2005)
  41. J Sen, et al., Alanine scanning mutagenesis of HIV-1 gp41 heptad repeat 1: Insight into the gp120-gp41 interaction. Biochemistry 49, 5057–5065 (2010). (10.1021/bi1005267) / Biochemistry / Alanine scanning mutagenesis of HIV-1 gp41 heptad repeat 1: Insight into the gp120-gp41 interaction by Sen J (2010)
  42. W Yuan, J Bazick, J Sodroski, Characterization of the multiple conformational states of free monomeric and trimeric human immunodeficiency virus envelope glycoproteins after fixation by cross-linker. J Virol 80, 6725–6737 (2006). (10.1128/JVI.00118-06) / J Virol / Characterization of the multiple conformational states of free monomeric and trimeric human immunodeficiency virus envelope glycoproteins after fixation by cross-linker by Yuan W (2006)
  43. X Wu, et al., Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010). (10.1126/science.1187659) / Science / Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1 by Wu X (2010)
  44. X Wu, et al., Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment. J Virol 83, 10892–10907 (2009). (10.1128/JVI.01142-09) / J Virol / Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment by Wu X (2009)
  45. R Diskin, et al., Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334, 1289–1293 (2011). (10.1126/science.1213782) / Science / Increasing the potency and breadth of an HIV antibody by using structure-based rational design by Diskin R (2011)
  46. M Pancera, R Wyatt, Selective recognition of oligomeric HIV-1 primary isolate envelope glycoproteins by potently neutralizing ligands requires efficient precursor cleavage. Virology 332, 145–156 (2005). (10.1016/j.virol.2004.10.042) / Virology / Selective recognition of oligomeric HIV-1 primary isolate envelope glycoproteins by potently neutralizing ligands requires efficient precursor cleavage by Pancera M (2005)
  47. EEH Tran, et al., Structural mechanism of trimeric HIV-1 envelope glycoprotein activation. PLoS Pathog 8, e1002797 (2012). (10.1371/journal.ppat.1002797) / PLoS Pathog / Structural mechanism of trimeric HIV-1 envelope glycoprotein activation by Tran EEH (2012)
  48. H Haim, I Salas, J Sodroski, Proteolytic processing of the human immunodeficiency virus envelope glycoprotein precursor decreases conformational flexibility. J Virol 87, 1884–1889 (2013). (10.1128/JVI.02765-12) / J Virol / Proteolytic processing of the human immunodeficiency virus envelope glycoprotein precursor decreases conformational flexibility by Haim H (2013)
  49. CM Carr, PS Kim, A spring-loaded mechanism for the conformational change of influenza hemagglutinin. Cell 73, 823–832 (1993). (10.1016/0092-8674(93)90260-W) / Cell / A spring-loaded mechanism for the conformational change of influenza hemagglutinin by Carr CM (1993)
  50. IA Wilson, JJ Skehel, DC Wiley, Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 289, 366–373 (1981). (10.1038/289366a0) / Nature / Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution by Wilson IA (1981)
  51. JM Binley, et al., A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure. J Virol 74, 627–643 (2000). (10.1128/JVI.74.2.627-643.2000) / J Virol / A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure by Binley JM (2000)
  52. X Yang, M Farzan, R Wyatt, J Sodroski, Characterization of stable, soluble trimers containing complete ectodomains of human immunodeficiency virus type 1 envelope glycoproteins. J Virol 74, 5716–5725 (2000). (10.1128/JVI.74.12.5716-5725.2000) / J Virol / Characterization of stable, soluble trimers containing complete ectodomains of human immunodeficiency virus type 1 envelope glycoproteins by Yang X (2000)
Dates
Type When
Created 12 years, 2 months ago (June 11, 2013, 5:14 p.m.)
Deposited 3 years, 2 months ago (June 7, 2022, 1:57 a.m.)
Indexed 2 months, 2 weeks ago (June 14, 2025, 10:46 a.m.)
Issued 12 years, 2 months ago (June 11, 2013)
Published 12 years, 2 months ago (June 11, 2013)
Published Online 12 years, 2 months ago (June 11, 2013)
Published Print 12 years, 1 month ago (July 23, 2013)
Funders 0

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@article{Mao_2013, title={Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer}, volume={110}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.1307382110}, DOI={10.1073/pnas.1307382110}, number={30}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Mao, Youdong and Wang, Liping and Gu, Christopher and Herschhorn, Alon and Désormeaux, Anik and Finzi, Andrés and Xiang, Shi-Hua and Sodroski, Joseph G.}, year={2013}, month=jun, pages={12438–12443} }