2021
DOI: 10.1101/2021.06.08.447516
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An atomistic model of the coronavirus replication-transcription complex as a hexamer assembled around nsp15

Abstract: Using available cryo-EM and x-ray crystal structures of the nonstructural proteins that are responsible for SARS-CoV-2 viral RNA replication and transcription, we have constructed an atomistic model of how the proteins assemble into a functioning superstructure.  Our principal finding is that the complex is hexameric, centered around nsp15.  The nsp15 hexamer is capped on two faces by trimers of nsp14/nsp16/(nsp10) 2 , where nsp14 is seen to undergo a large conformational change between its two domains.  Thi… Show more

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Cited by 3 publications
(4 citation statements)
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“…The viral-RNA replication mechanism is complex, involving RNA synthesis, proofreading, and capping and is mainly carried out by the minireplication transcription complex plus the error correction machinery (mRTC+ECM from here on referred to as RTC), having to survive against the human immune response. Cryo-EM techniques and computational methods have been immensely helpful in elucidating the overall structural organization of the RTC (Chen et al, 2020;Perry et al, 2021;Yan et al, 2021aYan et al, , 2020, but the high intrinsic flexibility, size and complexity of the non-structural proteins (nsps) arrangement entails that the overall resolution of the data is inherently poor. Consequently, the structure refinement workflows discard 30-40% of collected images from the existing RTC complex datasets (Chen et al, 2020;Yan et al, 2021aYan et al, , 2020, leaving significant gaps in our understanding.…”
Section: Overview Of the Problemmentioning
confidence: 99%
See 1 more Smart Citation
“…The viral-RNA replication mechanism is complex, involving RNA synthesis, proofreading, and capping and is mainly carried out by the minireplication transcription complex plus the error correction machinery (mRTC+ECM from here on referred to as RTC), having to survive against the human immune response. Cryo-EM techniques and computational methods have been immensely helpful in elucidating the overall structural organization of the RTC (Chen et al, 2020;Perry et al, 2021;Yan et al, 2021aYan et al, , 2020, but the high intrinsic flexibility, size and complexity of the non-structural proteins (nsps) arrangement entails that the overall resolution of the data is inherently poor. Consequently, the structure refinement workflows discard 30-40% of collected images from the existing RTC complex datasets (Chen et al, 2020;Yan et al, 2021aYan et al, , 2020, leaving significant gaps in our understanding.…”
Section: Overview Of the Problemmentioning
confidence: 99%
“…RTC System Preparation for all-atom simulations with NAMD. The SARS-CoV-2 RTC is a multi-subunit structure composed of several nsps, including the RNA-dependent RNA polymerase (RdRp, nsp12), Zinc-bound helicase (HEL, nsp13), the RNA-capping enzymes such as the nsp14 (N7-methyltransferase/MTase) and nsp16 (O2-MTase), the proofreading enzyme, namely nsp14, and uridylate-specific endoribonuclease activity (NendoU, nsp15) (Figure 3(a)) (Chen et al, 2020;Perry et al, 2021;Yan et al, 2021aYan et al, , 2020. Together they participate in the process of reproducing the viral genome (Wu et al, 2020).…”
Section: Innovations Realizedmentioning
confidence: 99%
“…The viral-RNA replication mechanism is complex, involving RNA synthesis, proofreading, and capping and is mainly carried out by the mini-replication transcription complex plus error correction machinery (mRTC+ECM from here on referred to as RTC), having to survive against the human immune response. Cryo-EM techniques and computational methods have been immensely helpful in elucidating the overall structural organization of the RTC (Chen et al, 2020, Perry et al, 2021, Yan et al, 2020, 2021a), but the high intrinsic flexibility, size and complexity of the nsp arrangement entails that the overall resolution of the data is inherently poor. Consequently, the structure refinement workflows discard 30-40% of collected images from the existing RTC complex datasets (Chen et al, 2020, Yan et al, 2020, 2021a), leaving significant gaps in our understanding.…”
Section: Overview Of the Problemmentioning
confidence: 99%
“…The SARS-CoV-2 RTC is a multi-subunit structure composed of several nsps, including the RNA-dependent RNA polymerase (RdRp, nsp12), Zinc-bound helicase (HEL, nsp13), the RNA-capping enzymes such as the nsp14 (N7-methyltransferase/MTase) and nsp16 (O2-MTase), the proofreading enzyme, namely nsp14, and uridylate-specific endoribonuclease activity (NendoU, nsp15)(Fig. 3A) (Chen et al, 2020, Perry et al, 2021, Yan et al, 2020, 2021a). Together they participate in the process of reproducing the viral genome (Wu et al, 2020).…”
Section: Innovations Realizedmentioning
confidence: 99%