Probing the Dynamic Structure–Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory
The SARS-CoV-2 main protease (Mpro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 Mpro crystal structures, are underway in many laboratories. However, little is known about the dynamic e...
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Published in | ACS pharmacology & translational science Vol. 3; no. 6; pp. 1111 - 1143 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
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American Chemical Society
11.12.2020
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Abstract | The SARS-CoV-2 main protease (Mpro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 Mpro crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced Mpro activation under nonequilibrium conditions. The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132–147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and Gly143 (comprising the second half of the oxyanion hole) reside. In particular, we observed the following: (1) Domain 3 undergoes dynamic rigid-body rotation about the domain 2–3 linker, alternately visiting two primary conformational states (denoted as M1 pro ↔ M2 pro); (2) The Gly143-containing crest of the m-shaped loop undergoes up and down translations caused by conformational changes within the rising stem of the loop (Lys137–Asn142) in response to domain 3 rotation and dimerization (denoted as M1/down pro ↔ 2·M2/up pro) (noting that the Cys145-containing crest is fixed in the up position). We propose that substrates associate to the M1/down pro state, which promotes the M2/down pro state, dimerization (denoted as 2·M2/up pro–substrate), and catalysis. Here, we explore the state transitions of Mpro under nonequilibrium conditions, the mechanisms by which they are powered, and the implications thereof for efficacious inhibition under in vivo conditions. |
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AbstractList | The SARS-CoV-2 main protease (Mpro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 Mpro crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced Mpro activation under nonequilibrium conditions. The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132–147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and Gly143 (comprising the second half of the oxyanion hole) reside. In particular, we observed the following: (1) Domain 3 undergoes dynamic rigid-body rotation about the domain 2–3 linker, alternately visiting two primary conformational states (denoted as M1 pro ↔ M2 pro); (2) The Gly143-containing crest of the m-shaped loop undergoes up and down translations caused by conformational changes within the rising stem of the loop (Lys137–Asn142) in response to domain 3 rotation and dimerization (denoted as M1/down pro ↔ 2·M2/up pro) (noting that the Cys145-containing crest is fixed in the up position). We propose that substrates associate to the M1/down pro state, which promotes the M2/down pro state, dimerization (denoted as 2·M2/up pro–substrate), and catalysis. Here, we explore the state transitions of Mpro under nonequilibrium conditions, the mechanisms by which they are powered, and the implications thereof for efficacious inhibition under in vivo conditions. The SARS-CoV-2 main protease (M pro ) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 M pro crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced M pro activation under nonequilibrium conditions . The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132–147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and Gly143 (comprising the second half of the oxyanion hole) reside. In particular, we observed the following: (1) Domain 3 undergoes dynamic rigid-body rotation about the domain 2–3 linker, alternately visiting two primary conformational states (denoted as M 1 pro ↔ M 2 pro ); (2) The Gly143-containing crest of the m-shaped loop undergoes up and down translations caused by conformational changes within the rising stem of the loop (Lys137–Asn142) in response to domain 3 rotation and dimerization (denoted as M 1/down pro ↔ 2·M 2/up pro ) (noting that the Cys145-containing crest is fixed in the up position). We propose that substrates associate to the M 1/down pro state, which promotes the M 2/down pro state, dimerization (denoted as 2·M 2/up pro –substrate), and catalysis. Here, we explore the state transitions of M pro under nonequilibrium conditions, the mechanisms by which they are powered, and the implications thereof for efficacious inhibition under in vivo conditions. The SARS-CoV-2 main protease (M ) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo and inhibitor-bound SARS-CoV/CoV-2 M crystal structures, are underway in many laboratories. However, little is known about the dynamic enzyme mechanism, which is needed to inform both assay development and structure-based inhibitor design. Here, we apply biodynamics theory to characterize the structural dynamics of substrate-induced M activation under nonequilibrium conditions. The catalytic cycle is governed by concerted dynamic structural rearrangements of domain 3 and the m-shaped loop (residues 132-147) on which Cys145 (comprising the thiolate nucleophile and half of the oxyanion hole) and Gly143 (comprising the second half of the oxyanion hole) reside. In particular, we observed the following: (1) Domain 3 undergoes dynamic rigid-body rotation about the domain 2-3 linker, alternately visiting two primary conformational states (denoted as M ↔ M ); (2) The Gly143-containing crest of the m-shaped loop undergoes up and down translations caused by conformational changes within the rising stem of the loop (Lys137-Asn142) in response to domain 3 rotation and dimerization (denoted as M ↔ 2·M ) (noting that the Cys145-containing crest is fixed in the up position). We propose that substrates associate to the M state, which promotes the M state, dimerization (denoted as 2·M -substrate), and catalysis. Here, we explore the state transitions of M under nonequilibrium conditions, the mechanisms by which they are powered, and the implications thereof for efficacious inhibition under conditions. |
Author | Wan, Hongbin Aravamuthan, Vibhas Pearlstein, Robert A |
AuthorAffiliation | Global Discovery Chemistry, Computer-Aided Drug Discovery Vibhas Aravamuthan – NIBR Informatics |
AuthorAffiliation_xml | – name: Global Discovery Chemistry, Computer-Aided Drug Discovery – name: Vibhas Aravamuthan – NIBR Informatics |
Author_xml | – sequence: 1 givenname: Hongbin orcidid: 0000-0002-4875-531X surname: Wan fullname: Wan, Hongbin organization: Global Discovery Chemistry, Computer-Aided Drug Discovery – sequence: 2 givenname: Vibhas surname: Aravamuthan fullname: Aravamuthan, Vibhas organization: Vibhas Aravamuthan – NIBR Informatics – sequence: 3 givenname: Robert A orcidid: 0000-0002-4313-8136 surname: Pearlstein fullname: Pearlstein, Robert A email: robert.pearlstein@novartis.com organization: Global Discovery Chemistry, Computer-Aided Drug Discovery |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33330838$$D View this record in MEDLINE/PubMed |
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CitedBy_id | crossref_primary_10_1016_j_drudis_2020_10_012 crossref_primary_10_1080_07391102_2021_1924271 crossref_primary_10_1021_acs_jcim_1c00449 crossref_primary_10_3389_fbinf_2021_717141 crossref_primary_10_1021_acsptsci_2c00138 crossref_primary_10_1107_S2059798322000948 crossref_primary_10_1007_s13346_021_01054_w |
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Snippet | The SARS-CoV-2 main protease (Mpro) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of... The SARS-CoV-2 main protease (M ) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of apo... The SARS-CoV-2 main protease (M pro ) is of major interest as an antiviral drug target. Structure-based virtual screening efforts, fueled by a growing list of... |
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Title | Probing the Dynamic Structure–Function and Structure-Free Energy Relationships of the Coronavirus Main Protease with Biodynamics Theory |
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