COVID-19 spike-host cell receptor GRP78 binding site prediction

Ibrahim M Ibrahim, Doaa H Abdelmalek, Mohammed E Elshahat, Abdo A Elfiky, Ibrahim M Ibrahim, Doaa H Abdelmalek, Mohammed E Elshahat, Abdo A Elfiky

Abstract

Objectives: Understanding the novel coronavirus (COVID-19) mode of host cell recognition may help to fight the disease and save lives. The spike protein of coronaviruses is the main driving force for host cell recognition.

Methods: In this study, the COVID-19 spike binding site to the cell-surface receptor (Glucose Regulated Protein 78 (GRP78)) is predicted using combined molecular modeling docking and structural bioinformatics. The COVID-19 spike protein is modeled using its counterpart, the SARS spike.

Results: Sequence and structural alignments show that four regions, in addition to its cyclic nature have sequence and physicochemical similarities to the cyclic Pep42. Protein-protein docking was performed to test the four regions of the spike that fit tightly in the GRP78 Substrate Binding Domain β (SBDβ). The docking pose revealed the involvement of the SBDβ of GRP78 and the receptor-binding domain of the coronavirus spike protein in recognition of the host cell receptor.

Conclusions: We reveal that the binding is more favorable between regions III (C391-C525) and IV (C480-C488) of the spike protein model and GRP78. Region IV is the main driving force for GRP78 binding with the predicted binding affinity of -9.8 kcal/mol. These nine residues can be used to develop therapeutics specific against COVID-19.

Keywords: BiP; COVID-19 spike; GRP78; Pep42; Protein-protein docking; Structural bioinformatics.

Conflict of interest statement

Declaration of Competing Interests All of the authors declare that there is no competing interest in this work.

Copyright © 2020. Published by Elsevier Ltd.

Figures

Fig. 1
Fig. 1
(A) Part of the multiple sequence alignment for the spike protein of all of the currently reported human coronaviruses strains (COVID-19, SARS, MERS, NL63, 229E, OC43, and HKU1). The alignment is made using the Clustal Omega web server and is displayed by ESpript 3 software. The red highlighted residues are identical, while yellow highlighted residues are conserved among the seven HCoVs. Secondary structures are represented at the top of the MSA for the COVID-19 spike, while the surface accessibility is shown at the bottom (blue, surface accessible, cyan, partially accessible, and white for buried residues). The four regions of the spike protein are shaded with green, blue, magenta, and red for regions I, II, III, and IV, respectively. (B) Structural superposition of SARS spike structure (green cartoon) and COVID-19 spike model (cyan cartoon). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
(A) Pairwise sequence alignment between Pep42 and four regions of the COVID-19 spike protein model. Secondary structures and surface accessibility are shown at the top and the bottom of the alignment, respectively. The percentage of identity arrows shows beta-sheets on the right side of each alignment. Identical and similar residues are highlighted in red and yellow, respectively. (B) The hydrophobicity index (Kyte & Doolittle) for the four regions of the spike protein model for COVID-19 and the Pep42 peptide. Grand average hydrophobicity (GRAVY) is shown on the right side for each peptide. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
(A) The structure of the spike protein model of COVID-19 in its homotrimer state (colored cartoon). Two chains, A (green) and B (cyan) are in the closed conformation, while chain C (magenta) is the open configuration that makes it able to recognize the host cell receptor. Region IV of the spike (C480-C488), which we suggest is the recognition site for cell-surface GRP78, is shown in the black cartoon in the enlarged panel. (B) The structure of the region III (black carton). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
The structure of the docking complexes of GRP78 (green cartoon) and COVID-19 spike (yellow cartoon) regions I and II (A) and regions III and IV (B). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
(A) The proposed binding mode of the host cell GRP78 (cyan surface) and the COVID-19 spike model (green surface) through region IV (C480-C488) (red surface). The amino acids from the GRP78 SBDβ that interact with the spike protein region IV (red cartoon) are labeled and represented in yellow sticks in the enlarged panel. (B) The proposed recognition mode of the COVID-19 spike (red surface) and cell-surface GRP78 (green surface) through the spike protein region C480-C488. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

References

    1. Hui D.S., I Azhar E., Madani T.A., Ntoumi F., Kock R., Dar O. Int J Infect Dis. 2020;91:264–266.
    1. Bogoch I.I., Watts A., Thomas-Bachli A., Huber C., Kraemer M.U.G., Khan K. Pneumonia of unknown etiology in Wuhan, China: potential for international spread via commercial air travel. J Travel Med. 2020
    1. Organization WH. World Health Organization; 2020. Surveillance case definitions for human infection with novel coronavirus ( nCoV): interim guidance v1, January 2020.
    1. Organization WH . World Health Organization; 2020. Laboratory testing of human suspected cases of novel coronavirus ( nCoV) infection: interim guidance, 10 January 2020.
    1. Organization WH . World Health Organization; 2020. Infection prevention and control during health care when novel coronavirus ( nCoV) infection is suspected: interim guidance, January 2020.
    1. Parr J. British Medical Journal Publishing Group; 2020. Pneumonia in China: lack of information raises concerns among Hong Kong health workers.
    1. Yang L. 2020. China confirms human-to-human transmission of coronavirus.
    1. Elfiky A.A., Mahdy S.M., Elshemey W.M. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses. J Med Virol. 2017;89(6):1040–1047.
    1. Chan J.F., Lau S.K., To K.K., Cheng V.C., Woo P.C., Yuen K.-.Y. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28(2):465–522.
    1. WHO. Middle East respiratory syndrome coronavirus (MERS-CoV). 23 june 2016 2016 (accessed 8 October 2016 2016).
    1. Hemida M.G., Alnaeem A. Some one health based control strategies for the middle east respiratory syndrome coronavirus. One Health. 2019;8
    1. Báez-Santos Y.M., Mielech A.M., Deng X., Baker S., Mesecar A.D. Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the middle east respiratory syndrome coronavirus. J Virol. 2014;88(21):12511–12527.
    1. Organization W.H. World Health Organization; 2019. Clinical management of severe acute respiratory infection when Middle East respiratory syndrome coronavirus ( MERS-CoV) infection is suspected: interim guidance.
    1. Ibrahim I.M., Abdelmalek D.H., Elfiky A.A. GRP78: a cell's response to stress. Life Sci. 2019;226:156–163.
    1. Belouzard S., Millet J.K., Licitra B.N., Whittaker G.R. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses. 2012;4(6):1011–1033.
    1. Lee A.S. The ER chaperone and signaling regulator GRP78/BIP as a monitor of endoplasmic reticulum stress. Methods. 2005;35(4):373–381.
    1. Li J., Lee A.S. Stress induction of GRP78/BIP and its role in cancer. Curr Mol Med. 2006;6(1):45–54.
    1. Rao R.V., Peel A., Logvinova A. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett. 2002;514(2–3):122–128.
    1. Quinones Q.J., Ridder G.G.D., Pizzo S.V. GRP78, a chaperone with diverse roles beyond the endoplasmic reticulum. Histol Histopathol. 2008
    1. Shen J., Chen X., Hendershot L., Prywes R. ER stress regulation of ATF6 localization by dissociation of BIP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell. 2002;3(1):99–111.
    1. Kim Y., Lillo A.M., Steiniger S.C. Targeting heat shock proteins on cancer cells: selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry. 2006;45(31):9434–9444.
    1. Berman H., Henrick K., Nakamura H. Announcing the worldwide protein data bank. Nat Struct Mol Biol. 2003;10(12):980.
    1. Chu H., Chan C.-.M., Zhang X. Middle East respiratory syndrome coronavirus and bat coronavirus HKU9 both can utilize GRP78 for attachment onto host cells. J Biol Chem. 2018;293(30):11709–11726.
    1. NCBI. National Center of Biotechnology Informatics (NCBI) database website. 2020. .
    1. Notredame C., Higgins D.G., Heringa J. T-Coffee: a novel method for fast and accurate multiple sequence alignment. J Mol Biol. 2000;302(1):205–217.
    1. Gouet P., Courcelle E., Stuart D.I., M√©toz F. ESPript: analysis of multiple sequence alignments in postscript. Bioinformatics. 1999;15(4):305–308.
    1. Biasini M., Bienert S., Waterhouse A. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42(W1):W252–W2W8.
    1. 1.7.6V. The PyMOL Molecular Graphics System, Version 1.7.6 Schrödinger, LLC.
    1. Gasteiger E., Hoogland C., Gattiker A., Wilkins M.R., Appel R.D., Bairoch A. The proteomics protocols handbook. Springer; 2005. Protein identification and analysis tools on the Expasy server; pp. 571–607.
    1. Yang J., Nune M., Zong Y., Zhou L., Liu Q. Close and allosteric opening of the polypeptide-binding site in a human HSP70 chaperone bip. Structure. 2015;23(12):2191–2203.
    1. Yang J., Zong Y., Su J. Conformation transitions of the polypeptide-binding pocket support an active substrate release from HSP70S. Nat Commun. 2017;8(1):1201.
    1. van Dijk A.D., Bonvin A.M. Solvated docking: introducing water into the modelling of biomolecular complexes. Bioinformatics. 2006;22(19):2340–2347.
    1. de Vries S.J., van Dijk M., Bonvin A.M. The Haddock web server for data-driven biomolecular docking. Nat Protoc. 2010;5(5):883–897.
    1. de Vries S.J., van Dijk A.D.J., Krzeminski M. HADDOCK versus HADDOCK: new features and performance of HADDOCK2.0 on the Capri targets. Proteins. 2007;69(4):726–733.
    1. van Dijk A.D., de Vries S.J., Dominguez C., Chen H., Zhou H.X., Bonvin A.M. Data-driven docking: HADDOCK's adventures in Capri. Proteins. 2005;60(2):232–238.
    1. Dominguez C., Boelens R., Bonvin A.M. HADDOCK: a protein− protein docking approach based on biochemical or biophysical information. J Am Chem Soc. 2003;125(7):1731–1737.
    1. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 2008;9(1):40.
    1. Yoneda Y., Steiniger S.C., Capkova K. A cell-penetrating peptidic GRP78 ligand for tumor cell-specific prodrug therapy. Bioorg Med Chem Lett. 2008;18(5):1632–1636.
    1. Kim Y., Lillo A.M., Steiniger S.C. Targeting heat shock proteins on cancer cells: selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry. 2006;45(31):9434–9444.
    1. Salentin S., Schreiber S., Haupt V.J., Adasme M.F., Schroeder M. PLIP: fully automated protein–ligand interaction profiler. Nucleic Acids Res. 2015;43(W1):W443–W4W7.
    1. Pujhari S., Macias V.M., Nissly R.H., Nomura M., Kuchipudi S.V., Rasgon J.L. Heat shock protein 70 (Hsp70) is involved in the Zika virus cellular infection process. bioRxiv. 2017

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