Neuraminidase structure

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A second example of up-and-down p sheets is the protein neuraminidase from influenza virus. Here the packing of the sheets is different from that in RBP. They do not form a simple barrel but instead six small sheets, each with four P strands, which are arranged like the blades of a six-bladed propeller. Loop regions between the p strands form the active site in the middle of one side of the propeller. Other similar structures are known with different numbers of the same motif arranged like propellers with different numbers of blades such as the G-proteins discussed in Chapter 13. 

Folding motifs form a propeller-like structure in neuraminidase... 

Figure S.7 The subunit structure of the neuraminidase headpiece (residues 84-469) from influenza virus is built up from six similar, consecutive motifs of four up-and-down antiparallel fi strands (Figure 5.6). Each such motif has been called a propeller blade and the whole subunit stmcture a six-blade propeller. The motifs are connected by loop regions from p strand 4 in one motif to p strand 1 in the next motif. The schematic diagram (a) is viewed down an approximate sixfold axis that relates the centers of the motifs. Four such six-blade propeller subunits are present in each complete neuraminidase molecule (see Figure 5.8). In the topological diagram (b) the yellow loop that connects the N-terminal P strand to the first P strand of motif 1 is not to scale. In the folded structure it is about the same length as the other loops that connect the motifs. (Adapted from J. Varghese et al.. Nature 303 35-40, 1983.)...

Figure 5.9 The six four-stranded motifs in a single subunit of neuraminidase form the six blades of a propeller-like structure. A schematic diagram of the subunit structure shows the propeller viewed from its side (a). An idealized propeller structure viewed from the side to highlight the position of the active site is shown in (b). The loop regions that connect the motifs (red in b) in combination with the loops that connect strands 2 and 3 within the motifs (green in b) form a wide funnel-shaped active site pocket, [(a) Adapted from P. Colman et ah, Nature 326 358-363, 1987.]...

The second protein in the membrane of influenza vims, neuraminidase, does not belong to any of these three groups of barrel structures. Instead, it forms a propeller-like structure of 24 p strands, arranged in six similar motifs that form the six blades of the propeller. Each motif is a p sheet of 4 up-and-down-connected p strands. The enzyme active site is formed by loop regions on one side of the propeller. 

Colman, P.M., Varghese, J.N., Laver, W.G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 303 41-44, 1983. 

Colman, P.M., et al. Three-dimensional structure of a complex of antibody with influenza virus neuraminidase. Nature 326 358-363, 1987. 

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B neuraminidase and its complex with sialic acid. Embo J 11 49-56 Burmeister WP, Henrissat B, Bosso C, Cusack S, Ruigrok RW (1993) Influenza B virus neuraminidase can synthesize its own inhibitor. Structure 1 19-26 Calfee DP, Hayden FG (1998) New approaches to influenza chemotherapy neuraminidase inhibitors, Drugs 56 537-553... 

Colman PM, Ward CW (1985) Structure and diversity of influenza virus neuraminidase. Curr Top Microbiol Immunol 114 177-255... 

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Kim CU, Lew W, Wilhams MA, Wu H, Zhang L, Chen X, Escarpe PA, Mendel DB, Laver WG, Stevens RC (1998) Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors, J Med Chem 41 2451-2460 Kim CU, Chen X, Mendel DB (1999) Neuraminidase inhibitors as anti-influenza virus agents. Antiviral Chem Chemother 10 141-154... 

Smith BJ, McKimm-Breshkin JL, McDonald M, Fernley RT, Varghese JN, Colman PM (2002) Structural studies of the resistance of influenza virus neuraminidase to inhibitors. J Med Chem... 

Stoll V, Stewart KD, Mating CJ, Muchmore S, Giranda V, Gu Y-GY, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL, Madigan DL, Xu Y, Saldivar A, Kati W, Laver G, Sowin T, Sham HL, Greer J, Kempf D (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry 42 718-727... 

Varghese IN, Colman PM (1991) Three-dimensional structure of the neuraminidase of influenza virus A/Tokyo/3/67 at 2.2 A resolution. 1 Mol Biol 221 473 86 Varghese IN, Laver WG, Colman PM (1983) Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution. Nature 303 35 0 Varghese IN, McKimm-Breschkin IL, Caldwell IB, Kortt AA, Colman PM (1992) The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins 14 327-332... 

Wang S-Q, Du Q-S, Chou K-C (2007) Study of drug resistance of chicken influenza A virus (H5N1) from homology-modeled 3D structures of neuraminidases. Biochem Biophys Res Commun 354 634-640... 

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