4xbd
From Proteopedia
1.45A resolution structure of Norovirus 3CL protease complex with a covalently bound dipeptidyl inhibitor (1R,2S)-2-({N-[(benzyloxy)carbonyl]-3-cyclohexyl-L-alanyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid (Orthorhombic P Form)
Structural highlights
Function[POLG_NVN68] Protein p48 may play a role in viral replication by interacting with host VAPA, a vesicle-associated membrane protein that plays a role in SNARE-mediated vesicle fusion. This interaction may target replication complex to intracellular membranes.[1] [2] NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity.[3] [4] Protein P22 may play a role in targeting replication complex to intracellular membranes.[5] [6] Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation.[7] [8] 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave host polyadenylate-binding protein thereby inhibiting cellular translation (By similarity).[9] [10] RNA-directed RNA polymerase replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This sgRNA encodes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).[11] [12] Publication Abstract from PubMedNorovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection. Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure-Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies.,Galasiti Kankanamalage AC, Kim Y, Weerawarna PM, Uy RA, Damalanka VC, Mandadapu SR, Alliston KR, Mehzabeen N, Battaile KP, Lovell S, Chang KO, Groutas WC J Med Chem. 2015 Mar 19. PMID:25761614[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Calicivirin | Alliston, K R | Battaile, K P | Chang, K O | Damalanka, V C | Groutas, W C | Kankanamalage, A C.G | Kim, Y | Lovell, S | Mandadapu, S R | Mehzabeen, N | Uy, R A.Z | Weerawarna, P M | Antiviral inhibitor | Dipeptidyl inhibitor | Hydrolase-hydrolase inhibitor complex | Norovirus | Norwalk virus | Protease
