Yang, Zhi and Wang, Haoqing and Liu, Albert Z. and Gristick, Harry B. and Bjorkman, Pamela J. (2019) Asymmetric opening of HIV-1 Env bound to CD4 and a coreceptor-mimicking antibody. Nature Structural & Molecular Biology, 26 (12). pp. 1167-1175. ISSN 1545-9985. https://resolver.caltech.edu/CaltechAUTHORS:20191023-154924044
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Abstract
The human immunodeficiency virus (HIV-1) envelope (Env) glycoprotein, a (gp120–gp41)₃ trimer, mediates fusion of viral and host cell membranes after gp120 binding to host receptor CD4. Receptor binding triggers conformational changes allowing coreceptor (CCR5) recognition through CCR5’s tyrosine-sulfated amino (N) terminus, release of the gp41 fusion peptide and fusion. We present 3.3 Å and 3.5 Å cryo-EM structures of E51, a tyrosine-sulfated coreceptor-mimicking antibody, complexed with a CD4-bound open HIV-1 native-like Env trimer. Two classes of asymmetric Env interact with E51, revealing tyrosine-sulfated interactions with gp120 mimicking CCR5 interactions, and two conformations of gp120–gp41 protomers (A and B protomers in AAB and ABB trimers) that differ in their degree of CD4-induced trimer opening and induction of changes to the fusion peptide. By integrating the new structural information with previous closed and open envelope trimer structures, we modeled the order of conformational changes on the path to coreceptor binding site exposure and subsequent viral–host cell membrane fusion.
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| Additional Information: | © 2019 Springer Nature Limited. Received 11 July 2019; Accepted 29 October 2019; Published 02 December 2019. We thank M. Farzan, A.P. West and C.O. Barnes for helpful discussions. Structural studies were performed in the Biological and Cryogenic Transmission Electron Microscopy Center at Caltech with assistance from directors A. Malyutin and S. Chen. We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support electron microscopy, Z. Yu (Janeila Farm) for advice on cryo-EM, J. Vielmetter and the Caltech Protein Expression Center for protein production, and M. Shahgholi and the Caltech Protein Exploration Laboratory for mass spectrometry analyses. This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health Grant No. HIVRAD P01 P01AI10014 (P.J.B.) and the National Institutes of Health Grant No. P50 8 P50 AI150464-13 (P.J.B.). Data availability: The structural coordinates were deposited into the Worldwide Protein Data Bank (wwPDB) with accession code 6U0L (class I E51–BG505 SOSIP.664–sCD4 complex) and 6U0N (class II E51–BG505 SOSIP.664–sCD4 complex). EM density maps were deposited into EMDB with accession numbers EMD-20605 (class I) and EMD-20608 (class II). Other data are available upon reasonable request. Author Contributions: Z.Y. and P.J.B. conceived the study. Z.Y. solved and interpreted cryo-EM structures with help from H.W. Z.Y., H.W., H.B.G. and P.J.B. analyzed the data. A.Z.L. and H.B.G. prepared and isolated E51 Fabs. Z.Y. and P.J.B. wrote the paper with contributions from other authors. The authors declare no competing interests. | |||||||||||||||||||||
| Errata: | 16 December 2019: In the version of this article initially published, in Fig. 6c,d the labels for the β-strands β2 and β3 were transposed. The error has been corrected in the HTML and PDF versions of the article. 21 January 2020: In the version of this article initially published, in Fig. 6b, top left panel, the β-sheet was labeled as a “Three-stranded bridging sheet.” The correct label is “Four-stranded bridging sheet.” The error has been corrected in the HTML and PDF versions of the article. | |||||||||||||||||||||
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| Subject Keywords: | Cryoelectron microscopy; Immunology | |||||||||||||||||||||
| Issue or Number: | 12 | |||||||||||||||||||||
| Record Number: | CaltechAUTHORS:20191023-154924044 | |||||||||||||||||||||
| Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:20191023-154924044 | |||||||||||||||||||||
| Official Citation: | Yang, Z., Wang, H., Liu, A.Z. et al. Asymmetric opening of HIV-1 Env bound to CD4 and a coreceptor-mimicking antibody. Nat Struct Mol Biol 26, 1167–1175 (2019) doi:10.1038/s41594-019-0344-5 | |||||||||||||||||||||
| Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | |||||||||||||||||||||
| ID Code: | 99425 | |||||||||||||||||||||
| Collection: | CaltechAUTHORS | |||||||||||||||||||||
| Deposited By: | George Porter | |||||||||||||||||||||
| Deposited On: | 02 Dec 2019 18:26 | |||||||||||||||||||||
| Last Modified: | 03 Aug 2020 22:26 |
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