tetano
Editor, Senior Moderator
Biophys J
. 2021 Mar 29;S0006-3495(21)00254-X.
doi: 10.1016/j.bpj.2021.03.024. Online ahead of print.
SARS-CoV2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential
Neha Vithani[SUP] 1 [/SUP], Michael D Ward[SUP] 1 [/SUP], Maxwell I Zimmerman[SUP] 1 [/SUP], Borna Novak[SUP] 2 [/SUP], Jonathan H Borowsky[SUP] 1 [/SUP], Sukrit Singh[SUP] 1 [/SUP], Gregory R Bowman[SUP] 3 [/SUP]
Affiliations
Abstract
Coronaviruses have caused multiple epidemics in the past two decades, in addition to the current COVID-19 pandemic that is severely damaging global health and the economy. Coronaviruses employ between twenty and thirty proteins to carry out their viral replication cycle including infection, immune evasion, and replication. Among these, nonstructural protein 16 (Nsp16), a 2'-O-methyltransferase, plays an essential role in immune evasion. Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA to enhance translation efficiency and distinguish self from other. Unlike human CMTr1, Nsp16 requires a binding partner, Nsp10, to activate its enzymatic activity. The requirement of this binding partner presents two questions that we investigate in this manuscript. First, how does Nsp10 activate Nsp16? While experimentally-derived structures of the active Nsp16/Nsp10 complex exist, structures of inactive, monomeric Nsp16 have yet to be solved. Therefore, it is unclear how Nsp10 activates Nsp16. Using over one millisecond of molecular dynamics simulations of both Nsp16 and its complex with Nsp10, we investigate how the presence of Nsp10 shifts Nsp16's conformational ensemble in order to activate it. Second, guided by this activation mechanism and Markov state models (MSMs), we investigate if Nsp16 adopts inactive structures with cryptic pockets that, if targeted with a small molecule, could inhibit Nsp16 by stabilizing its inactive state. After identifying such a pocket in SARS-CoV2 Nsp16, we show that this cryptic pocket also opens in SARS-CoV1 and MERS, but not in human CMTr1. Therefore, it may be possible to develop pan-coronavirus antivirals that target this cryptic pocket.
. 2021 Mar 29;S0006-3495(21)00254-X.
doi: 10.1016/j.bpj.2021.03.024. Online ahead of print.
SARS-CoV2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential
Neha Vithani[SUP] 1 [/SUP], Michael D Ward[SUP] 1 [/SUP], Maxwell I Zimmerman[SUP] 1 [/SUP], Borna Novak[SUP] 2 [/SUP], Jonathan H Borowsky[SUP] 1 [/SUP], Sukrit Singh[SUP] 1 [/SUP], Gregory R Bowman[SUP] 3 [/SUP]
Affiliations
- PMID: 33794150
- DOI: 10.1016/j.bpj.2021.03.024
Abstract
Coronaviruses have caused multiple epidemics in the past two decades, in addition to the current COVID-19 pandemic that is severely damaging global health and the economy. Coronaviruses employ between twenty and thirty proteins to carry out their viral replication cycle including infection, immune evasion, and replication. Among these, nonstructural protein 16 (Nsp16), a 2'-O-methyltransferase, plays an essential role in immune evasion. Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA to enhance translation efficiency and distinguish self from other. Unlike human CMTr1, Nsp16 requires a binding partner, Nsp10, to activate its enzymatic activity. The requirement of this binding partner presents two questions that we investigate in this manuscript. First, how does Nsp10 activate Nsp16? While experimentally-derived structures of the active Nsp16/Nsp10 complex exist, structures of inactive, monomeric Nsp16 have yet to be solved. Therefore, it is unclear how Nsp10 activates Nsp16. Using over one millisecond of molecular dynamics simulations of both Nsp16 and its complex with Nsp10, we investigate how the presence of Nsp10 shifts Nsp16's conformational ensemble in order to activate it. Second, guided by this activation mechanism and Markov state models (MSMs), we investigate if Nsp16 adopts inactive structures with cryptic pockets that, if targeted with a small molecule, could inhibit Nsp16 by stabilizing its inactive state. After identifying such a pocket in SARS-CoV2 Nsp16, we show that this cryptic pocket also opens in SARS-CoV1 and MERS, but not in human CMTr1. Therefore, it may be possible to develop pan-coronavirus antivirals that target this cryptic pocket.