BACKGROUND Streptococcus pneumoniae Neuraminidase A (NanA) is a multi-domain protein anchored to the bacterial surface. Upstream of the catalytic domain of NanA is a domain that conforms to the sialic acid-recognising CBM40 family of the CAZY (carbohydrate-active enzymes) database. This domain has been identified to play a critical role in allowing the bacterium to promote adhesion and invasion of human brain microvascular endothelial cells, and hence may play a key role in promoting bacterial meningitis. In addition, the CBM40 domain has also been reported to activate host chemokines and neutrophil recruitment during infection. RESULTS Crystal structures of both apo- and holo- forms of the NanA CBM40 domain (residues 121 to 305), have been determined to 1.8 Å resolution. The domain shares the fold of other CBM40 domains that are associated with sialidases. When in complex with α2,3- or α2,6-sialyllactose, the domain is shown to interact only with the terminal sialic acid. Significantly, a deep acidic pocket adjacent to the sialic acid-binding site is identified, which is occupied by a lysine from a symmetry-related molecule in the crystal. This pocket is adjacent to a region that is predicted to be involved in protein-protein interactions. CONCLUSIONS The structural data provide the details of linkage-independent sialyllactose binding by NanA CBM40 and reveal striking surface features that may hold the key to recognition of binding partners on the host cell surface. The structure also suggests that small molecules or sialic acid analogues could be developed to fill the acidic pocket and hence provide a new therapeutic avenue against meningitis caused by S. pneumoniae.

中文翻译：

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NanA唾液酸酶的碳水化合物结合模块的结构表征，一种肺炎球菌毒力因子。

背景技术肺炎链球菌神经氨酸酶A(NanA)是一种锚定在细菌表面的多结构域蛋白。NanA的催化结构域的上游是符合CAZY（碳水化合物活性酶）数据库的唾液酸识别CBM40家族的结构域。该结构域已被确定在允许细菌促进人脑微血管内皮细胞的粘附和侵袭中起关键作用，因此可能在促进细菌性脑膜炎中起关键作用。此外，据报道 CBM40 结构域在感染期间激活宿主趋化因子和中性粒细胞募集。结果 NanA CBM40 结构域（残基 121 至 305）的脱辅基形式和全息形式的晶体结构已确定为 1.8 Å 分辨率。该结构域共享与唾液酸酶相关的其他 CBM40 结构域的折叠。当与 α2,3- 或 α2,6-唾液酸乳糖复合时，显示该结构域仅与末端唾液酸相互作用。重要的是，确定了与唾液酸结合位点相邻的深酸性口袋，该口袋被晶体中对称相关分子的赖氨酸占据。该口袋与预计参与蛋白质-蛋白质相互作用的区域相邻。结论 结构数据提供了 NanA CBM40 与连接无关的唾液乳糖结合的详细信息，并揭示了引人注目的表面特征，这些特征可能是识别宿主细胞表面上的结合伴侣的关键。