9ldu
Crystal structure of HCoV 229E main protease in complex with Oridonin
Structural highlights
FunctionR1AB_CVH22 The replicase polyprotein of coronaviruses is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products. The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3 (By similarity). The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Also contains an ADP-ribose-1-phosphate (ADRP)-binding function (By similarity). The helicase which contains a zinc finger structure displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Its ATPase activity is strongly stimulated by poly(U), poly(dT), poly(C), poly(dA), but not by poly(G). The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction (By similarity). Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter (By similarity). Nsp9 is a ssRNA-binding protein (By similarity). NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond (By similarity). Publication Abstract from PubMedCurrently, there are seven coronaviruses that can infect humans: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, Middle East respiratory syndrome coronavirus, human coronavirus 229E (HCoV-229E), HCoV-NL63, HCoV-HKUl, and HCoV-OC43. The coronavirus pandemic, especially highly pathogenic coronaviruses such as SARS-CoV-2, has caused severe damage to human health and the social economy. Therefore, the development of broad-spectrum drugs is critical to address the current unmet urgent clinical need and to contain potential future coronaviruses. The conserved main protease (M(pro)) of coronavirus is critical for virus replication and has been considered an ideal drug target. Here, we identified a natural compound, oridonin, that shows broad-spectrum inhibition of the M(pro)s of SARS-CoV-2, SARS-CoV, HCoV-NL63, and HCoV-229E and can also inhibit the mutant of SARS-CoV-2's M(pro) (G15S: Lambda variant). The inhibitory effect of oridonin highly depends on the covalent modification of the electrophilic enone structure to the cysteine residue (Cys144/Cys145) in the active site of the M(pro). The crystal structure of the HCoV-229E complex with oridonin was first determined by X-ray crystallography, and we compared it with the previously reported structure of SARS-CoV-2 M(pro) complexes with oridonin. Molecular dynamics simulations further demonstrated that oridonin stably binds to both SARS-CoV-2 Máµráµ and HCoV-229E M(pro). Through detailed structural biological analysis, we revealed that oridonin blocks substrate binding through a unique nonpeptidomimetic covalent binding mode. Overall, our data provide evidence that oridonin can serve as a lead compound for the design of a covalent inhibitor against the coronavirus. Structural basis for the inhibition of the coronavirus main protease by oridonin.,Zeng P, Zhou X, Guo L, Li W, Li J Biophys J. 2026 Mar 3;125(5):1247-1256. doi: 10.1016/j.bpj.2026.01.029. Epub 2026 , Jan 22. PMID:41578642[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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