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Source of High Pathogenicity of an Avian Influenza Virus H5N1: Why H5 Is Better Cleaved by Furin

Panita Decha ^*, Thanyada Rungrotmongkol ^*, Pathumwadee Intharathep ^*, Maturos Malaisree ^*, Ornjira Aruksakunwong , Chittima Laohpongspaisan ^*, Vudhichai Parasuk ^*, Pornthep Sompornpisut ^*, Somsak Pianwanit ^*, Sirirat Kokpol ^* and Supot Hannongbua ^*

^* Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok 10330, Thailand; and Department of Chemistry, Faculty of Science, Rangsit University, Pathumtani 12000, Thailand

Correspondence: Address reprint requests to Supot Hannongbua, E-mail: supot.h{at}chula.ac.th.

The origin of the high pathogenicity of an emerging avian influenza H5N1 due to the –RRRKK– insertion at the cleavage loop of the hemagglutinin H5, was studied using the molecular dynamics technique, in comparison with those of the noninserted H5 and H3 bound to the furin (FR) active site. The cleavage loop of the highly pathogenic H5 was found to bind strongly to the FR cavity, serving as a conformation suitable for the proteolytic reaction. With this configuration, the appropriate interatomic distances were found for all three reaction centers of the enzyme-substrate complex: the arrangement of the catalytic triad, attachment of the catalytic Ser³⁶⁸ to the reactive S1-Arg, and formation of the oxyanion hole. Experimentally, the –RRRKK– insertion was also found to increase in cleavage of hemagglutinin by FR. The simulated data provide a clear answer to the question of why inserted H5 is better cleaved by FR than the other subtypes, explaining the high pathogenicity of avian influenza H5N1.

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