Source of high pathogenicity of an avian influenza virus H5N1: why H5 is better cleaved by furin.
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 Ser(368) 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.
Decha
Panita
P
Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok 10330, Thailand.
Rungrotmongkol
Thanyada
T
Intharathep
Pathumwadee
P
Malaisree
Maturos
M
Aruksakunwong
Ornjira
O
Laohpongspaisan
Chittima
C
Parasuk
Vudhichai
V
Sompornpisut
Pornthep
P
Pianwanit
Somsak
S
Kokpol
Sirirat
S
Hannongbua
Supot
S
D003198:Computer Simulation; D045683:Furin / Q000737:chemistry* / Q000648:ultrastructure*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000648:ultrastructure*; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry* / Q000472:pathogenicity* / Q000648:ultrastructure; D008956:Models, Chemical; D008958:Models, Molecular; D010447:Peptide Hydrolases / Q000737:chemistry / Q000648:ultrastructure
D019267:Hemagglutinin Glycoproteins, Influenza Virus; C109963:hemagglutinin, avian influenza A virus; D010447:Peptide Hydrolases; D045683:Furin