Preprint PUBDB-2020-01727

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Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

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2020
Zenodo

Zenodo () [10.1101/2020.05.02.043554]  GO

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Abstract: Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.


Note: PrePrint: https://www.biorxiv.org/content/10.1101/2020.05.02.043554

Contributing Institute(s):
  1. CFEL-Coherent X-Ray Imaging (FS-CFEL-1)
  2. FS-CFEL-1 (Group Leader: Henry Chapman) (CFEL-I)
  3. Arwen Pearson - CUI (CFEL-TRSB)
  4. Experimentebetreuung PETRA III (FS-PET-D)
  5. Informationstechnologie (IT)
  6. MPSD (CFEL-ARD)
  7. Nanolab (FS-NL)
  8. EMBL (EMBL)
  9. beauftragt von UNI (UNI/CUI)
  10. Uni Hamburg / Physik (UNI/PHY)
Research Program(s):
  1. 6215 - Soft Matter, Health and Life Sciences (POF3-621) (POF3-621)
  2. HIDSS-0002 - DASHH: Data Science in Hamburg - Helmholtz Graduate School for the Structure of Matter (2019_IVF-HIDSS-0002) (2019_IVF-HIDSS-0002)
Experiment(s):
  1. PETRA Beamline P11 (PETRA III)
  2. Experiments at CFEL

Appears in the scientific report 2020
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The record appears in these collections:
Private Collections > >Extern > >HAS-User > >FS-UNI > UNI/CUI
Private Collections > >Extern > >HAS-User > >FS-UNI > UNI/PHY
Private Collections > >DESY > >FH > >IT > IT
Private Collections > >CFEL > >UNI-CFEL > CFEL-TRSB
Private Collections > >CFEL > >FS-CFEL > CFEL-I
Private Collections > >CFEL > >MPSD > CFEL-ARD
Private Collections > >DESY > >FS > FS-CFEL-1
Private Collections > >DESY > >FS > FS-PET-D
Private Collections > >DESY > >FS > FS-NL
Private Collections > >EMBL > EMBL
Document types > Reports > Preprints
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Raw diffraction data (CBF) for a structure of SARS-CoV-2 Main Protease bound to 2-Methyl-1-tetralone
Zenodo () [10.5281/ZENODO.3752540]  GO BibTeX | EndNote: XML, Text | RIS


 Record created 2020-05-05, last modified 2025-07-29


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