Preprint

PUBDB-2025-02613

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Statistical crystallography reveals an allosteric network in SARS-CoV-2 M pro

Creon, A.CFEL*EMBL*DESY* ; Scheer, T. E. S.CFEL*DESY* ; Reinke, P.CFEL*DESY* ; Rahmani Mashhour, A.CFEL*DESY* ; Günther, S.CFEL*XFEL.EU*DESY* ; Niebling, S.Extern*CSSB* ; Schamoni-Kast, K.Extern*CSSB*XFEL.EU* ; Uetrecht, C.CSSB*XFEL.EU* ; Meents, A.CFEL*XFEL.EU*DESY* ; Chapman, H. N.CFEL*XFEL.EU*DESY* ; Sprenger, J.CFEL*DESY* ; Lane, T. (Corresponding author)CFEL*Extern*DESY*

2025

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Please use a persistent id in citations: doi:10.1101/2025.01.28.635305

Abstract: To interpret and transmit biological signals, proteins use correlated motions. Experimental determination of these dynamics with atomic resolution remains a key challenge. Here, using thousands of crystals of the main protease (Mpro) from SARS-CoV-2, we were able to infer a model of the protein’s correlated motions. Mpro is regulated by concentration, becoming enzymatically active after forming a homodimer. To understand the correlated motions that enable dimerization to activate catalysis, we employed our model, predicting which regions of the dimerization domain are structurally linked to the active site. Mutations at these positions, expected to disrupt catalysis, resulted in a dramatic reduction in activity in one case, a mild effect in the second, and none in the third. Additional crystallography and biophysical experiments provide a mechanistic explanation for these results. Our work suggests that a statistical crystallography can determine protein correlated motions and rationalize their biological function.

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Contributing Institute(s):

1. FS-CFEL-1 (Group Leader: Henry Chapman) (CFEL-I)
2. FS-CFEL-1 Fachgruppe BMX (FS-CFEL-1-BMX)
3. DOOR-User (DOOR ; HAS-User)

Research Program(s):

1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
2. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
3. AIM, DFG project G:(GEPRIS)390715994 - EXC 2056: CUI: Advanced Imaging of Matter (390715994) (390715994)
4. 05K19GU4 - SFX2: Hochdurchsatz Serielle-Femtosekunden Kristallographie @ EU XFEL. (BMBF-05K19GU4) (BMBF-05K19GU4)
5. InternLabs-0011 - HIR3X - Helmholtz International Laboratory on Reliability, Repetition, Results at the most advanced X-ray Sources (2020_InternLabs-0011) (2020_InternLabs-0011)
6. ARIADNE - Redefining mass spectrometry – a breakthrough platform for real-time noninvasive breath analysis with single ion detection of intact viruses and bacteria and post-analysis molecular characterization (964553) (964553)
7. SPOCkS MS - Sampling Protein cOmplex Conformational Space with native top down Mass Spectrometry (759661) (759661)

Experiment(s):

1. PETRA Beamline P11 (PETRA III)

Appears in the scientific report 2025

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