9m6u | pdb_00009m6u
Crystal structure of SARS-Cov-2 main protease M49I mutant in complex with Pomotrelvir
Structural highlights
FunctionR1AB_SARS2 Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7] Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7] May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7] Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7] Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7] Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN] (PubMed:32198291). Also able to bind an ADP-ribose-1-phosphate (ADRP).[UniProtKB:P0C6X7][1] Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7] Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7] Responsible for replication and transcription of the viral RNA genome.[UniProtKB:P0C6X7] Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[UniProtKB:P0C6X7] Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens.[UniProtKB:P0C6X7] Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[UniProtKB:P0C6X7] Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[UniProtKB:P0C6X7] Publication Abstract from PubMedAlthough the SARS-CoV-2 pandemic has passed, the continuous emergence of variants and the repeated occurrence of coronaviral pandemics in the past make the development of broad-spectrum anti-coronavirus drugs crucial. M(pro) is an ideal target for the treatment of coronavirus. Pomotrelvir is a novel M(pro) inhibitor that has completed phase II clinical trials. This study systematically evaluated the inhibitory efficacy and binding mechanism of Pomotrelvir against SARS-CoV-2 M(pro) and six mutants (E166R, E166N, H163A, S46F, M49I, V186F) through enzymatic experiments, crystal structure analysis, and molecular dynamics simulations. The results indicated that the inhibitory activity of Pomotrelvir against the mutants was significantly reduced compared to the wild type (116 to 208 times), but still retained micromolar-level inhibitory capacity. In detail, E166R, E166N, H163A, S46F, M49I, and V186F result in reduced binding affinity and inhibitory effects of Pomotrelvir due to the disruption of hydrogen bonds, changes in binding conformation, and reduced stability of the complex conformation. An interesting discovery is that Pomotrelvir is exclusively present in the protomer B of the H163A mutant, where the binding pocket exhibits significant expansion and enhanced negative charge. This study reveals the structural basis by which Pomotrelvir maintains its inhibitory activity against M(pro) mutants through covalent inhibition mechanisms and dynamic interaction networks, providing an important theoretical basis for optimizing the design of broad-spectrum antiviral drugs against coronaviruses and addressing drug resistance mutations. Structural basis and inhibitory mechanism of the interaction between pomotrelvir and SARS-CoV-2 main protease mutants.,Zhou X, Guo L, Li W, Zeng P, Li J Int J Biol Macromol. 2025 Dec 31;339(Pt 2):149954. doi: , 10.1016/j.ijbiomac.2025.149954. PMID:41482225[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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