Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases

Varghese, Joseph; Colman, Peter M.; Donkelaar, A. van; Blick, Tony; Sahasrabudhe, Anjali; McKimm-Breschkin, Jennifer L.

doi:10.1073/pnas.94.22.11808

Cited by 120 publications

(163 citation statements)

References 39 publications

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“…An HB site was created in the non-hemagglutinating N2 NA by substituting amino acids from two loops of N9 NA into N2 NA 58 . In N9 NA, an X-ray crystal structure (Figure 3) showed a sialic acid molecule bound in the predicted HB site, contacting amino acids Ser367, Ser370, Ser372, Asn400, Trp403 and Lys432 (N2 numbering) 59 . This site bears no resemblance to either the NA active site or the HA sialic acid binding site, and indeed the specificity of binding is unlike that of HA, in that the bound sialic acid is not released by N9 or N2 NA activity but only by bacterial sialidases of very broad specificity 60 .…”

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

“…HB activity was also found in the N1 NA of fowl plague virus 61 . Comparisons of sequences in the area of the second binding site suggested that avian viruses have the HB activity while human viruses do not 59,61,62 , but so far a specific function of the HB activity in bird viruses has not been established.…”

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

“…Under a variety of soaking conditions, sialic acid was seen bound in both the active site and the HB site of all four monomers. In the active site the sialic acid is in the twisted boat conformation that may result from its tight binding preceding catalysis 22,63,64 , while the sialic acid in the HB site is in the chair conformation as in N9 NB site and in HA 32,59 . Interestingly, although sialic acid in solution exists 95% as the β anomer, only the α configuration is seen in the HB binding site (Figure 3), which may explain the difficulty in locating the second sialic acid in N9 NA and the high concentration of sialic acid needed before the sialic acid is clearly seen.…”

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

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Influenza neuraminidase

Air

2011

Influenza Resp Viruses

208

216

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Influenza neuraminidase is the target of two licensed antivirals that have been very successful, with several more in development. However, neuraminidase has been largely ignored as a vaccine target despite evidence that inclusion of neuraminidase in the subunit vaccine gives increased protection. This article describes current knowledge on the structure, enzyme activity and antigenic significance of neuraminidase.

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Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

Section: Some Nas Have a Second Sialic Acid Binding Sitementioning

confidence: 99%

See 1 more Smart Citation

Influenza neuraminidase

Air

2011

Influenza Resp Viruses

208

216

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“…We ran these 3 programs and recorded score values for the top ranked poses whose RMSD's from crystal structures are under 2.0 Å. The experimental IC50 values for the featured inhibitors are taken from literature [23][24][25][26][27][28] and converted to binding affinities. Table 1 shows calculated binding affinities along with the experimental values.…”

Section: Resultsmentioning

confidence: 99%

Importance of Accurate Charges in Binding Affinity Calculations: A Case of Neuraminidase Series

Park¹,

Sung²,

Cho³

2013

Bulletin of the Korean Chemical Society

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It has been shown that calculating atomic charges using quantum mechanical level theory greatly improves the accuracy of docking. A protocol was developed and shown to be effective. That this protocol works is just a manifestation of the fact that electrostatic interactions are important in protein-ligand binding. In order to investigate how the same protocol helps in prediction of binding affinities, we took a series of known cocrystal structures of influenza neuraminidase inhibitors with the receptor and performed docking with Glide SP, Glide XP, and QPLD, the last being a workflow that incorporates QM/MM calculations to replace the fixed atomic charges of force fields with quantum mechanically recalculated ones at a given docking pose, and predicted the binding affinities of each cocrystal. The correlation with experimental binding affinities considerably improved with QPLD compared to Glide SP/XP yielding r 2 = 0.83. The results suggest that for binding sites, such as that of neuraminidase, which are laden with hydrophilic residues, protocols such as QPLD which utilizes QM-based atomic charges can better predict the binding affinities.

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“…II, III). In addition to having few anti-NA antibody determinants as proposed for strain 575 [22,24], further examinations [10,11,13,31,32] may find that certain NDV strains may have an HA and perhaps a second NA binding site; such is the case with the frequently isolated [23] avian influenza subtype 9 [50].…”

Section: Discussionmentioning

confidence: 99%

Agglutination-separation reactions of red blood cells sensitized with Newcastle disease virus: quantities, agglutination characteristics, and serology of altered virus and HN spikes released following neuraminidase reactivation

Graves

2001

Vet. Res.

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-Red blood cells (RBC) become sensitized following the elution of strain 575 Newcastle disease virus (NDV). The neuraminidase (NA) in the haemagglutinin (HA)-sialic acid configuration is inactive. The HA on sensitized RBC agglutinates normal RBC. The sialic acid on normal RBC initiated reactivation of the NA-a newly described function. Then normal-sensitized RBC agglomerates separated at 37 o C in the irreversible agglutination-separation (AS) reactions. With separation the AS products, HN spikes (150-200 kDa) and altered NDV, which contain fewer HN spikes than intact allantoic NDV, were removed from the sensitized RBC and the NDV membrane. Extraction of HN spikes from the membrane required more sialic acid than the removal of AS products from RBC. Thus 2 reactions were delineated for the orderly removal. Amounts of each released AS product suggest the source of the HN spikes. AS reactions and ether treatment of NDV increased the HA titres up to 19.2 fold. HA-sialic acid configurations were estimated by the amounts of normal RBC agglutinated by sensitized RBC and also by agglutination with fetuin. Elution of B1 vaccine, HN spikes from ether-treated NDV as well as AS products separated on sephadex resulted in incompletely sensitized RBC; fewer configurations were titrated with normal RBC; all failed to respond to anti-NA antibody. In contrast, sensitized RBC or suspensions of 575 NDV, but not the B1 vaccine strain, responded to both anti-NA and anti-HA antibody. Sensitization, slow elution, and responding to anti-NA antibody, which was accompanied by fluorescent foci on sensitized RBC, required intact NDV and the infrequent HA-sialic acid configuration. The NA was inactive for the HA-sialic acid configuration but cleaved fetuin, indicating substrate specificity. An inactive NA would allow time for fusion and NDV penetration rather than elution by an active NA early in NDV infection.Newcastle disease virus / agglutination-separation reactions of sensitized RBC / neuraminidase reactivation / new sialic acid function / HN serologic configurations Vet. Res. 32 (2001) 475-489 475

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Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases

Cited by 120 publications

References 39 publications

Influenza neuraminidase

Influenza neuraminidase

Importance of Accurate Charges in Binding Affinity Calculations: A Case of Neuraminidase Series

Agglutination-separation reactions of red blood cells sensitized with Newcastle disease virus: quantities, agglutination characteristics, and serology of altered virus and HN spikes released following neuraminidase reactivation

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