Crystal structures of glycoprotein D of equine alphaherpesviruses reveal potential binding sites to the entry receptor MHC-I

Viviane Kremling; Bernhard Loll; Szymon Pach; Ismail Dahmani; Christoph Weise; Gerhard Wolber; Salvatore Chiantia; Markus C Wahl; Nikolaus Osterrieder; Walid Azab

doi:10.3389/fmicb.2023.1197120

Crystal structures of glycoprotein D of equine alphaherpesviruses reveal potential binding sites to the entry receptor MHC-I

Front Microbiol. 2023 May 11:14:1197120. doi: 10.3389/fmicb.2023.1197120. eCollection 2023.

Authors

Viviane Kremling¹, Bernhard Loll², Szymon Pach³, Ismail Dahmani⁴, Christoph Weise⁵, Gerhard Wolber³, Salvatore Chiantia⁴, Markus C Wahl^{2

6}, Nikolaus Osterrieder^{1

7}, Walid Azab¹

Affiliations

¹ Institut für Virologie, Robert von Ostertag-Haus, Zentrum für Infektionsmedizin, Freie Universität Berlin, Berlin, Germany.
² Laboratory of Structural Biochemistry, Freie Universität Berlin, Berlin, Germany.
³ Institute of Pharmacy (Pharmaceutical Chemistry), Freie Universität Berlin, Berlin, Germany.
⁴ Universität Potsdam, Institut für Biochemie und Biologie, Potsdam, Brandenburg, Germany.
⁵ BioSupraMol Core Facility, Bio-Mass Spectrometry, Freie Universität Berlin, Berlin, Germany.
⁶ Helmholtz-Zentrum Berlin für Materialien und Energie, Macromolecular Crystallography, Berlin, Germany.
⁷ Department of Infectious Diseases and Public Health, City University of Hong Kong, Kowloon, Hong Kong SAR, China.

Abstract

Cell entry of most alphaherpesviruses is mediated by the binding of glycoprotein D (gD) to different cell surface receptors. Equine herpesvirus type 1 (EHV-1) and EHV-4 gDs interact with equine major histocompatibility complex I (MHC-I) to initiate entry into equine cells. We have characterized the gD-MHC-I interaction by solving the crystal structures of EHV-1 and EHV-4 gDs (gD1, gD4), performing protein-protein docking simulations, surface plasmon resonance (SPR) analysis, and biological assays. The structures of gD1 and gD4 revealed the existence of a common V-set immunoglobulin-like (IgV-like) core comparable to those of other gD homologs. Molecular modeling yielded plausible binding hypotheses and identified key residues (F213 and D261) that are important for virus binding. Altering the key residues resulted in impaired virus growth in cells, which highlights the important role of these residues in the gD-MHC-I interaction. Taken together, our results add to our understanding of the initial herpesvirus-cell interactions and will contribute to the targeted design of antiviral drugs and vaccine development.

Keywords: alphaherpesviruses; glycoprotein D; host-pathogen interaction; receptor binding; virus entry.