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Molecular Dynamics of DHHC20 Acyltransferase Suggests Principles of Lipid and Protein Substrate Selectivity.
Panina, Irina; Krylov, Nikolay; Gadalla, Mohamed Rasheed; Aliper, Elena; Kordyukova, Larisa; Veit, Michael; Chugunov, Anton; Efremov, Roman.
  • Panina I; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
  • Krylov N; International Laboratory for Supercomputer Atomistic Modelling and Multi-Scale Analysis, National Research University Higher School of Economics, 101000 Moscow, Russia.
  • Gadalla MR; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
  • Aliper E; International Laboratory for Supercomputer Atomistic Modelling and Multi-Scale Analysis, National Research University Higher School of Economics, 101000 Moscow, Russia.
  • Kordyukova L; Department of Veterinary Medicine, Institute of Virology, Free University Berlin, 14163 Berlin, Germany.
  • Veit M; Department of Virology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt.
  • Chugunov A; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
  • Efremov R; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.
Int J Mol Sci ; 23(9)2022 May 03.
Article in English | MEDLINE | ID: covidwho-1820295
ABSTRACT
Lipid modification of viral proteins with fatty acids of different lengths (S-acylation) is crucial for virus pathogenesis. The reaction is catalyzed by members of the DHHC family and proceeds in two

steps:

the autoacylation is followed by the acyl chain transfer onto protein substrates. The crystal structure of human DHHC20 (hDHHC20), an enzyme involved in the acylation of S-protein of SARS-CoV-2, revealed that the acyl chain may be inserted into a hydrophobic cavity formed by four transmembrane (TM) α-helices. To test this model, we used molecular dynamics of membrane-embedded hDHHC20 and its mutants either in the absence or presence of various acyl-CoAs. We found that among a range of acyl chain lengths probed only C16 adopts a conformation suitable for hDHHC20 autoacylation. This specificity is altered if the small or bulky residues at the cavity's ceiling are exchanged, e.g., the V185G mutant obtains strong preferences for binding C18. Surprisingly, an unusual hydrophilic ridge was found in TM helix 4 of hDHHC20, and the responsive hydrophilic patch supposedly involved in association was found in the 3D model of the S-protein TM-domain trimer. Finally, the exchange of critical Thr and Ser residues in the spike led to a significant decrease in its S-acylation. Our data allow further development of peptide/lipid-based inhibitors of hDHHC20 that might impede replication of Corona- and other enveloped viruses.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Acyltransferases / COVID-19 Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23095091

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Acyltransferases / COVID-19 Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23095091