4KS1

Influenza neuraminidase in complex with antiviral compound (3S,4R,5R)-4-(acetylamino)-3-amino-5-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid

Summary for 4KS1

• Entry DOI: 10.2210/pdb4ks1/pdb
• Related: 4KS2 4KS3 4KS4 4KS5
• Descriptor: Neuraminidase, CALCIUM ION, (3S,4R,5R)-4-(acetylamino)-3-amino-5-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid, ... (5 entities in total)
• Functional Keywords: sialidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Influenza A virus (Influenza Virus)
• Total number of polymer chains: 1
• Total formula weight: 43742.30

Authors

Kerry, P.S.,Russell, R.J.M. (deposition date: 2013-05-17, release date: 2013-10-30, Last modification date: 2024-11-06)

Primary citation

Kerry, P.S.,Mohan, S.,Russell, R.J.,Bance, N.,Niikura, M.,Pinto, B.M.
Structural basis for a class of nanomolar influenza A neuraminidase inhibitors.
Sci Rep, 3:2871-2871, 2013

PubMed Abstract: The influenza virus neuraminidase (NA) is essential for the virus life cycle. The rise of resistance mutations against current antiviral therapies has increased the need for the development of novel inhibitors. Recent efforts have targeted a cavity adjacent to the catalytic site (the 150-cavity) in addition to the primary catalytic subsite in order to increase specificity and reduce the likelihood of resistance. This study details structural and in vitro analyses of a class of inhibitors that bind uniquely in both subsites. Crystal structures of three inhibitors show occupation of the 150-cavity in two distinct and novel binding modes. We believe these are the first nanomolar inhibitors of NA to be characterized in this way. Furthermore, we show that one inhibitor, binding within the catalytic site, offers reduced susceptibility to known resistance mutations via increased flexibility of a pendant pentyloxy group and the ability to pivot about a strong hydrogen-bonding network.

PubMed: 24129600
DOI: 10.1038/srep02871

Experimental method

X-RAY DIFFRACTION (2.2 Å)