5T6D

2.10 A resolution structure of Norovirus 3CL protease in complex with the dipeptidyl inhibitor 7l (hexagonal form)

Summary for 5T6D

• Entry DOI: 10.2210/pdb5t6d/pdb
• Related: 5T6F 5T6G
• Descriptor: Genome polyprotein, 3-cyclohexyl-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-N~2~-{[3-(4-methoxyphenoxy)propyl]sulfonyl}-L- alaninamide (3 entities in total)
• Functional Keywords: protease, norovirus, norwalk virus, antiviral inhibitors, dipeptidyl inhibitor, protease-protease inhibitor complex, protease/protease inhibitor
• Biological source: Norwalk virus (Hu/NV/NV/1968/US)
• Total number of polymer chains: 2
• Total formula weight: 41331.63

Authors

Lovell, S.,Battaile, K.P.,Mehzabeen, N.,Kankanamalage, A.C.G.,Kim, Y.,Rathnayake, A.D.,Damalanka, V.C.,Weerawarna, P.M.,Doyle, S.T.,Alsoudi, A.F.,Dissanayake, D.M.P.,Chang, K.-O.,Groutas, W.C. (deposition date: 2016-09-01, release date: 2016-11-23, Last modification date: 2024-11-20)

Primary citation

Galasiti Kankanamalage, A.C.,Kim, Y.,Rathnayake, A.D.,Damalanka, V.C.,Weerawarna, P.M.,Doyle, S.T.,Alsoudi, A.F.,Dissanayake, D.M.,Lushington, G.H.,Mehzabeen, N.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C.
Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors.
Eur J Med Chem, 126:502-516, 2016

PubMed Abstract: Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.

PubMed: 27914364
DOI: 10.1016/j.ejmech.2016.11.027

Experimental method

X-RAY DIFFRACTION (2.1 Å)