About: Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CL(pro)): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS

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About: Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CL(pro)): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CL(pro)): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS
Creator	Mesecar, Andrew Tomar, Sakshi Denison, Mark Ghosh, Arun John, Johnston, Melanie Nyalapatla, Prasanth Osswald, Heather Paul, Lake St, Sarah
Source	Medline; PMC
abstract	All coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the β-CoV subgroup, require the proteolytic activity of the nsp5 protease (also known as 3C-like protease, 3CL(pro)) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CL(pro) from other β-CoV 2c members, including HKU4 and HKU5, MERS-CoV 3CL(pro) is less efficient at processing a peptide substrate due to MERS-CoV 3CL(pro) being a weakly associated dimer. Conversely, HKU4, HKU5, and SARS-CoV 3CL(pro) enzymes are tightly associated dimers. Analytical ultracentrifugation studies support that MERS-CoV 3CL(pro) is a weakly associated dimer (K(d) ∼52 μm) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CL(pro) were synthesized and utilized in analytical ultracentrifugation experiments and demonstrate that MERS-CoV 3CL(pro) undergoes significant ligand-induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at a low compound concentration as a result of induced dimerization. Primary sequence comparisons and x-ray structural analyses of two MERS-CoV 3CLpro and inhibitor complexes, determined to 1.6 Å, reveal remarkable structural similarity of the dimer interface with 3CL(pro) from HKU4-CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long range interactions by the nonconserved amino acids distant from the dimer interface may control MERS-CoV 3CL(pro) dimerization. Activation of MERS-CoV 3CL(pro) through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CL(pro) inhibitors as antiviral agents.
has issue date	2015-06-08(xsd:dateTime)
bibo:doi	10.1074/jbc.m115.651463
bibo:pmid	26055715
has license	bronze-oa
sha1sum (hex)	a72987263c3b602888680fd3bab5f92a8725a23b
schema:url	https://doi.org/10.1074/jbc.m115.651463
resource representing a document's title	Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CL(pro)): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS
has PubMed Central identifier	PMC4528106
has PubMed identifier	26055715
schema:publication	Journal of Biological Chemistry
resource representing a document's body	covid:a72987263c3b602888680fd3bab5f92a8725a23b#body_text
is schema:about of	named entity 'NSP5' named entity 'ANTIVIRALS' named entity 'pro' named entity 'Conclusion' named entity 'polyprotein' named entity 'polyprotein' named entity 'pro' named entity 'MECHANISM' named entity 'INDUCED' named entity 'DEVELOPMENT' named entity 'ACTIVATION' named entity 'KEY' named entity 'RESULTS' named entity 'REGULATING' named entity 'CONCLUSION' named entity 'COMPLEXITY' named entity 'PROTEASE' named entity 'LIGAND' named entity 'LIGAND BINDING' named entity 'DIMERIZATION' named entity 'REQUIRED' named entity 'ADD' named entity 'DEVELOPMENT' named entity 'PRO' named entity 'PRO' named entity 'MIDDLE EAST RESPIRATORY SYNDROME ' named entity 'PROTEASE' named entity 'ASSOCIATED' named entity 'PROCESSING' named entity 'POLYPROTEIN' named entity 'REGULATION' named entity 'DIMER' named entity 'IS A' named entity 'LIGAND' named entity 'ANTIVIRALS' named entity 'INHIBITORS' named entity 'ACTIVE' named entity 'MERS-COV' named entity 'SIGNIFICANCE' named entity 'ENZYMATIC ACTIVITY' named entity 'CORONAVIRUS' named entity 'BACKGROUND' named entity 'FORMATION' named entity 'INDUCED' named entity 'DIMERIZATION' covid:arg/a72987263c3b602888680fd3bab5f92a8725a23b named entity 'pro' named entity 'binding' named entity 'dimer' named entity 'MERS-CoV' named entity 'enzyme' named entity 'crystal structures' named entity 'Crystallization' named entity 'dimer' named entity 'SARS-CoV' named entity 'X-ray diffraction' named entity 'coronavirus infections' named entity 'MERS-CoV' named entity 'enzymatic activity' named entity 'K I' named entity 'antivirals' named entity 'processing' named entity 'Ligand' named entity 'MERS-CoV' named entity 'MERS-CoV' named entity 'enzymatic activity' named entity 'dimerization' named entity 'protease' named entity 'nsp5' named entity 'Coronavirus' named entity 'Middle East Respiratory Syndrome' named entity 'MERS'

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