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Structural basis for substrate specificity and catalysis of α1,6-fucosyltransferase.
Nature Communications ( IF 14.7 ) Pub Date : 2020-02-20 , DOI: 10.1038/s41467-020-14794-z Ana García-García 1 , Laura Ceballos-Laita 1 , Sonia Serna 2, 3 , Raik Artschwager 2, 3 , Niels C Reichardt 2, 3, 4 , Francisco Corzana 5 , Ramon Hurtado-Guerrero 1, 6, 7, 8
Nature Communications ( IF 14.7 ) Pub Date : 2020-02-20 , DOI: 10.1038/s41467-020-14794-z Ana García-García 1 , Laura Ceballos-Laita 1 , Sonia Serna 2, 3 , Raik Artschwager 2, 3 , Niels C Reichardt 2, 3, 4 , Francisco Corzana 5 , Ramon Hurtado-Guerrero 1, 6, 7, 8
Affiliation
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Core-fucosylation is an essential biological modification by which a fucose is transferred from GDP-β-L-fucose to the innermost N-acetylglucosamine residue of N-linked glycans. A single human enzyme α1,6-fucosyltransferase (FUT8) is the only enzyme responsible for this modification via the addition of an α-1,6-linked fucose to N-glycans. To date, the details of substrate recognition and catalysis by FUT8 remain unknown. Here, we report the crystal structure of FUT8 complexed with GDP and a biantennary complex N-glycan (G0), which provides insight into both substrate recognition and catalysis. FUT8 follows an SN2 mechanism and deploys a series of loops and an α-helix which all contribute in forming the binding site. An exosite, formed by one of these loops and an SH3 domain, is responsible for the recognition of branched sugars, making contacts specifically to the α1,3 arm GlcNAc, a feature required for catalysis. This information serves as a framework for inhibitor design, and helps to assess its potential as a therapeutic target.
中文翻译：
底物特异性和α1,6-岩藻糖基转移酶催化的结构基础。
核心岩藻糖基化是必不可少的生物学修饰，通过该修饰，岩藻糖可从GDP-β-L-岩藻糖转移到N-连接聚糖最内层的N-乙酰氨基葡萄糖残基上。单一的人类酶α1,6-岩藻糖基转移酶（FUT8）是通过向N-聚糖中添加α-1,6-连接的岩藻糖来进行这种修饰的唯一酶。迄今为止，FUT8识别和催化底物的细节仍然未知。在这里，我们报告FUT8的晶体结构与GDP和双天线配合物N-聚糖（G0）的复合，提供对底物识别和催化的洞察力。FUT8遵循SN2机制，并部署了一系列有助于形成结合位点的环和α-螺旋。由这些环之一和SH3结构域形成的异位点负责识别分支糖，专门与α1,3臂GlcNAc接触，这是催化所需的功能。该信息用作抑制剂设计的框架，并有助于评估其作为治疗靶标的潜力。
更新日期：2020-02-20
中文翻译：
底物特异性和α1,6-岩藻糖基转移酶催化的结构基础。
核心岩藻糖基化是必不可少的生物学修饰，通过该修饰，岩藻糖可从GDP-β-L-岩藻糖转移到N-连接聚糖最内层的N-乙酰氨基葡萄糖残基上。单一的人类酶α1,6-岩藻糖基转移酶（FUT8）是通过向N-聚糖中添加α-1,6-连接的岩藻糖来进行这种修饰的唯一酶。迄今为止，FUT8识别和催化底物的细节仍然未知。在这里，我们报告FUT8的晶体结构与GDP和双天线配合物N-聚糖（G0）的复合，提供对底物识别和催化的洞察力。FUT8遵循SN2机制，并部署了一系列有助于形成结合位点的环和α-螺旋。由这些环之一和SH3结构域形成的异位点负责识别分支糖，专门与α1,3臂GlcNAc接触，这是催化所需的功能。该信息用作抑制剂设计的框架，并有助于评估其作为治疗靶标的潜力。
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