4XBD

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)

Summary for 4XBD

• Entry DOI: 10.2210/pdb4xbd/pdb
• Related: 4XBB 4XBD
• Descriptor: 3C-LIKE PROTEASE, (1R,2S)-2-({N-[(benzyloxy)carbonyl]-3-cyclohexyl-L-alanyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid (3 entities in total)
• Functional Keywords: protease, norovirus, norwalk virus, antiviral inhibitors, dipeptidyl inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Norwalk virus (strain GI/Human/United States/Norwalk/1968) (Hu/NV/NV/1968/US)
• Cellular location: Protein p48: Host membrane ; Single-pass membrane protein . NTPase: Host membrane ; Single- pass membrane protein . Protein p22: Host membrane ; Single-pass membrane protein : Q83883
• Total number of polymer chains: 2
• Total formula weight: 41303.49

Authors

Lovell, S.,Battaile, K.P.,Mehzabeen, N.,Kankanamalage, A.C.G.,Kim, Y.,Weerawarna, P.M.,Uy, R.A.Z.,Damalanka, V.C.,Mandadapu, S.R.,Alliston, K.R.,Groutas, W.C.,Chang, K.-O. (deposition date: 2014-12-16, release date: 2015-03-25, Last modification date: 2024-11-13)

Primary citation

Galasiti Kankanamalage, A.C.,Kim, Y.,Weerawarna, P.M.,Uy, R.A.,Damalanka, V.C.,Mandadapu, S.R.,Alliston, K.R.,Mehzabeen, N.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
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.
J.Med.Chem., 58:3144-3155, 2015

PubMed Abstract: Norovirus 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.

PubMed: 25761614
DOI: 10.1021/jm5019934

Experimental method

X-RAY DIFFRACTION (1.45 Å)