Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Is amyloid fibrillation related to 3D domain swapping for the C-terminal domain of SARS-CoV main protease?

ABSTRACT: The C-terminal domain of SARS-CoV main protease (M^pro-C) can form 3D domain-swapped dimer by exchanging the α₁-helices fully buried inside the protein hydrophobic core, under non-denaturing conditions. Here, we report that M^pro-C can also form amyloid fibrils under the 3D domain-swappable conditions in vitro, and the fibrils are not formed through runaway/propagated domain swapping. It is found that there are positive correlations between the rates of domain swapping dimerization and amyloid fibrillation at different temperatures, and for different mutants. However, some M^pro-C mutants incapable of 3D domain swapping can still form amyloid fibrils, indicating that 3D domain swapping is not essential for amyloid fibrillation. Furthermore, NMR H/D exchange data and molecular dynamics simulation results suggest that the protofibril core region tends to unpack at the early stage of 3D domain swapping, so that the amyloid fibrillation can proceed during the 3D domain swapping process. We propose that 3D domain swapping makes it possible for the unpacking of the amyloidogenic fragment of the protein and thus accelerates the amyloid fibrillation process kinetically, which explains the well-documented correlations between amyloid fibrillation and 3D domain swapping observed in many proteins.

SUBMITTER: Yuan Z

PROVIDER: S-EPMC8694786 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

C-terminal domain of SARS-CoV main protease can form a 3D domain-swapped dimer.

Project description:SARS coronavirus main protease (M(pro)) plays an essential role in the extensive proteolytic processing of the viral polyproteins (pp1a and pp1ab), and it is an important target for anti-SARS drug development. We have reported that both the M(pro) C-terminal domain alone (M(pro)-C) and the N-finger deletion mutant of M(pro) (M(pro)-Delta7) exist as a stable dimer and a stable monomer (Zhong et al., J Virol 2008; 82:4227-4234). Here, we report structures of both M(pro)-C monomer and dimer. The structure of the M(pro)-C monomer is almost identical to that of the C-terminal domain in the crystal structure of M(pro). Interestingly, the M(pro)-C dimer structure is characterized by 3D domain-swapping, in which the first helices of the two protomers are interchanged and each is enwrapped by four other helices from the other protomer. Each folding subunit of the M(pro)-C domain-swapped dimer still has the same general fold as that of the M(pro)-C monomer. This special dimerization elucidates the structural basis for the observation that there is no exchange between monomeric and dimeric forms of M(pro)-C and M(pro)-Delta7.

| S-EPMC2762595 | biostudies-literature

The Molecular Mechanism of Domain Swapping of the C-Terminal Domain of the SARS-Coronavirus Main Protease.

Project description:In three-dimensional domain swapping, two protein monomers exchange a part of their structures to form an intertwined homodimer, whose subunits resemble the monomer. Several viral proteins domain swap to increase their structural complexity or functional avidity. The main protease (Mpro) of the severe acute respiratory syndrome (SARS) coronavirus proteolyzes viral polyproteins and has been a target for anti-SARS drug design. Domain swapping in the α-helical C-terminal domain of Mpro (MproC) locks Mpro into a hyperactive octameric form that is hypothesized to promote the early stages of viral replication. However, in the absence of a complete molecular understanding of the mechanism of domain swapping, investigations into the biological relevance of this octameric Mpro have stalled. Isolated MproC can exist as a monomer or a domain-swapped dimer. Here, we investigate the mechanism of domain swapping of MproC using coarse-grained structure-based models and molecular dynamics simulations. Our simulations recapitulate several experimental features of MproC folding. Further, we find that a contact between a tryptophan in the MproC domain-swapping hinge and an arginine elsewhere forms early during folding, modulates the folding route, and promotes domain swapping to the native structure. An examination of the sequence and the structure of the tryptophan containing hinge loop shows that it has a propensity to form multiple secondary structures and contacts, indicating that it could be stabilized into either the monomer- or dimer-promoting conformations by mutations or ligand binding. Finally, because all residues in the tryptophan loop are identical in SARS-CoV and SARS-CoV-2, mutations that modulate domain swapping may provide insights into the role of octameric Mpro in the early-stage viral replication of both viruses.

| S-EPMC7837137 | biostudies-literature

1H, 13C and 15N resonance assignments of SARS-CoV main protease N-terminal domain.

Project description:The main protease (M(pro)) of severe acute respiratory syndrome coronavirus (SARS-CoV) plays an essential role in the extensive proteolytic processing of the viral polyproteins (pp1a and pp1ab), and it is an important target for anti-SARS drug development. SARS-CoV M(pro) is composed of a catalytic N-terminal domain and an ?-helical C-terminal domain linked by a long loop. Even though the N-terminal domain of SARS-CoV M(pro) adopts a similar chymotrypsin-like fold as that of piconavirus 3C protease, the extra C-terminal domain is required for SARS-CoV M(pro) to be enzymatically active. Here, we reported the NMR assignments of the SARS-CoV M(pro) N-terminal domain alone, which are essential for its solution structure determination.

| S-EPMC7091140 | biostudies-literature

Three-dimensional domain swapping as a mechanism to lock the active conformation in a super-active octamer of SARS-CoV main protease.

Project description:Proteolytic processing of viral polyproteins is indispensible for the lifecycle of coronaviruses. The main protease (M(pro)) of SARS-CoV is an attractive target for anti-SARS drug development as it is essential for the polyprotein processing. M(pro) is initially produced as part of viral polyproteins and it is matured by autocleavage. Here, we report that, with the addition of an N-terminal extension peptide, M(pro) can form a domain-swapped dimer. After complete removal of the extension peptide from the dimer, the mature M(pro) self-assembles into a novel super-active octamer (AO-M(pro)). The crystal structure of AO-M(pro) adopts a novel fold with four domain-swapped dimers packing into four active units with nearly identical conformation to that of the previously reported M(pro) active dimer, and 3D domain swapping serves as a mechanism to lock the active conformation due to entanglement of polypeptide chains. Compared with the previously well characterized form of M(pro), in equilibrium between inactive monomer and active dimer, the stable AO-M(pro) exhibits much higher proteolytic activity at low concentration. As all eight active sites are bound with inhibitors, the polyvalent nature of the interaction between AO-M(pro) and its polyprotein substrates with multiple cleavage sites, would make AO-M(pro) functionally much more superior than the M(pro) active dimer for polyprotein processing. Thus, during the initial period of SARS-CoV infection, this novel active form AOM(pro) should play a major role in cleaving polyproteins as the protein level is extremely low. The discovery of AOM(pro) provides new insights about the functional mechanism of M(pro) and its maturation process.

| S-EPMC4875095 | biostudies-literature

Potential SARS-CoV-2 main protease inhibitors.

Project description:The coronavirus disease 2019 (COVID-19) pandemic has prompted an urgent need for new treatment strategies. No target-specific drugs are currently available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but new drug candidates targeting the viral replication cycle are being explored. A prime target of drug-discovery efforts is the SARS-CoV-2 main protease (Mpro). The main proteases of different coronaviruses, including SARS-CoV-2, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), share a structurally conserved substrate-binding region that can be exploited to design new protease inhibitors. With the recent reporting of the X-ray crystal structure of the SARS-CoV-2 Mpro, studies to discover Mpro inhibitors using both virtual and in vitro screening are progressing rapidly. This review focusses on the recent developments in the search for small-molecule inhibitors targeting the SARS-CoV-2 Mpro.

| S-EPMC7724992 | biostudies-literature

In silico prediction of SARS-CoV-2 main protease and polymerase inhibitors: 3D-Pharmacophore modelling.

Project description:The outbreak of the second severe acute respiratory syndrome coronavirus (SARS-CoV-2) known as COVID-19 has caused global concern. No effective vaccine or treatment to control the virus has been approved yet. Social distancing and precautionary protocols are still the only way to prevent person-to-person transmission. We hope to identify anti-COVID-19 activity of the existing drugs to overcome this pandemic as soon as possible. The present study used HEX and AutoDock Vina softwares to predict the affinity of about 100 medicinal structures toward the active site of 3-chymotrypsin-like protease (3Clpro) and RNA-dependent RNA polymerase (RdRp), separately. Afterwards, MOE software and the pharmacophore-derived query methodology were employed to determine the pharmacophore model of their inhibitors. Tegobuvir (19) and compound 45 showed the best binding affinity toward RdRp and 3Clpro of SARS-CoV-2 in silico, respectively. Tegobuvir -previously applied for hepatitis C virus- formed highly stable complex with uncommon binding pocket of RdRp (E total: -707.91 Kcal/mol) in silico. In addition to compound 45, tipranavir (28) and atazanavir (26) as FDA-approved HIV protease inhibitors were tightly interacted with the active site of SARS-CoV-2 main protease as well. Based on pharmacophore modelling, a good structural pattern for potent candidates against SARS-CoV-2 main enzymes is suggested. Re-tasking or taking inspiration from the structures of tegobuvir and tipranavir can be a proper approach toward coping with the COVID-19 in the shortest possible time and at the lowest cost.Communicated by Ramaswamy H. Sarma.

| S-EPMC7898304 | biostudies-literature

Topological analysis of SARS CoV-2 main protease.

Project description:There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (Mpro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free Mpro shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SARS CoV-2 Mpro is 1900% more sensitive than SARS CoV-1 Mpro in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of Mpro to structural perturbations is located exactly around the catalytic site Cys-145 and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 Mpro.

| S-EPMC7286701 | biostudies-literature

Perspectives on SARS-CoV-2 Main Protease Inhibitors.

Project description:The main protease (Mpro) plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and is highly conserved, rendering it one of the most attractive therapeutic targets for SARS-CoV-2 inhibition. Currently, although two drug candidates targeting SARS-CoV-2 Mpro designed by Pfizer are under clinical trials, no SARS-CoV-2 medication is approved due to the long period of drug development. Here, we collect a comprehensive list of 817 available SARS-CoV-2 and SARS-CoV Mpro inhibitors from the literature or databases and analyze their molecular mechanisms of action. The structure-activity relationships (SARs) among each series of inhibitors are discussed. Additionally, we broadly examine available antiviral activity, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and animal tests of these inhibitors. We comment on their druggability or drawbacks that prevent them from becoming drugs. This Perspective sheds light on the future development of Mpro inhibitors for SARS-CoV-2 and future coronavirus diseases.

| S-EPMC9357291 | biostudies-literature

Drug development targeting SARS-CoV-2 main protease.

Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants are responsible for the devastating coronavirus disease 2019 (COVID-19) pandemic with more than 6.5 million deaths since 2019. Although a number of vaccines significantly reduced the mortality rate, a large number of the world population is yet being infected with highly contagious omicron variants/subvarints. Additional therapeutic interventions are needed to reduce hospitalization and curb the ongoing pandemic. The activity of the SARS-CoV-2 enzyme; chymotrypsin-like main protease (Mpro) is essential for the cleavage of viral nonstructural polypeptides into individual functional proteins and therefore Mpro is an attractive drug target. The aim of this review is to summarize recent progress toward the development of therapeutic drugs against Mpro protease.

| S-EPMC9773221 | biostudies-literature

Domain swapping and amyloid fibril conformation.

Project description:For several different proteins an apparent correlation has been observed between the propensity for dimerization by domain-swapping and the ability to aggregate into amyloid-like fibrils. Examples include the disease-related proteins β 2-microglobulin and transthyretin. This has led to proposals that the amyloid-formation pathway may feature extensive domain swapping. One possible consequence of such an aggregation pathway is that the resulting fibrils would incorporate structural elements that resemble the domain-swapped forms of the protein and, thus, reflect certain native-like structures or domain-interactions. In magic angle spinning solid-state NMR-based and other structural studies of such amyloid fibrils, it appears that many of these proteins form fibrils that are not native-like. Several fibrils, instead, have an in-register, parallel conformation, which is a common amyloid structural motif and is seen, for instance, in various prion fibrils. Such a lack of native structure in the fibrils suggests that the apparent connection between domain-swapping ability and amyloid-formation may be more subtle or complex than may be presumed at first glance.

| S-EPMC3399535 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data