Antigen recognition by single-domain antibodies: structural latitudes and constraints.
Antigen recognition by single-domain antibodies: structural latitudes and constraints.
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DOI：
10.1080/19420862.2018.1489633
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发表时间：
2018
期刊：
影响因子：
5.3
通讯作者：
MacKenzie CR
中科院分区：
文献类型：
--
作者：
Henry KA;MacKenzie CR
单结构域抗体（sdAb）是骆驼科有蹄类动物和软骨鱼类天然产生的仅重链抗体的自主可变结构域，其已经进化为仅使用三个互补决定区（CDR）环而不是常规VH：VL抗体中存在的六个环来结合抗原。基于有限的证据，已经提出sdAb可以采用互补位结构，该互补位结构使它们倾向于优先识别凹陷的蛋白质表位，但识别突起的表位和小分子较差或不识别。在这里，我们全面调查了支持这一假设的证据。我们发现与常规抗体的互补位形状相比，sdAb的互补位形状存在全局结构差异的一些支持：sdAb互补位具有较小的分子表面积和直径，更常见地具有非典型的CDR 1和CDR 2结构，并且具有延长的CDR 3长度分布，但具有相似的氨基酸组成，并且不比常规抗体互补位延伸更多（从CDR碱基到尖端测量的原子间距离）。与同源抗原复合的sdAb和常规抗体的X射线晶体结构的比较表明，sdAb和常规抗体在蛋白质上掩埋类似的溶剂暴露的表面积，并形成类似类型的非共价相互作用，尽管这些更集中在紧凑的sdAb互补位中。因此，sdAb可能具有特权进入蛋白质上的不同抗原区域，但这仅仅是由于它们的小分子尺寸，而不是由于分子识别机制的一般差异。围绕所谓的sdAb不能结合小分子的证据不太清楚。现有的数据提供了一个结构框架，了解自主重链抗体的进化出现和功能。
Single-domain antibodies (sdAbs), the autonomous variable domains of heavy chain-only antibodies produced naturally by camelid ungulates and cartilaginous fishes, have evolved to bind antigen using only three complementarity-determining region (CDR) loops rather than the six present in conventional VH:VL antibodies. It has been suggested, based on limited evidence, that sdAbs may adopt paratope structures that predispose them to preferential recognition of recessed protein epitopes, but poor or non-recognition of protuberant epitopes and small molecules. Here, we comprehensively surveyed the evidence in support of this hypothesis. We found some support for a global structural difference in the paratope shapes of sdAbs compared with those of conventional antibodies: sdAb paratopes have smaller molecular surface areas and diameters, more commonly have non-canonical CDR1 and CDR2 structures, and have elongated CDR3 length distributions, but have similar amino acid compositions and are no more extended (interatomic distance measured from CDR base to tip) than conventional antibody paratopes. Comparison of X-ray crystal structures of sdAbs and conventional antibodies in complex with cognate antigens showed that sdAbs and conventional antibodies bury similar solvent-exposed surface areas on proteins and form similar types of non-covalent interactions, although these are more concentrated in the compact sdAb paratope. Thus, sdAbs likely have privileged access to distinct antigenic regions on proteins, but only owing to their small molecular size and not to general differences in molecular recognition mechanism. The evidence surrounding the purported inability of sdAbs to bind small molecules was less clear. The available data provide a structural framework for understanding the evolutionary emergence and function of autonomous heavy chain-only antibodies.
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影响因子：
4.8
作者：
De Genest, E;Silence, K;Muyldermans, S
通讯作者：
Muyldermans, S
影响因子：
5.8
作者：
Burgess SG;Oleksy A;Cavazza T;Richards MW;Vernos I;Matthews D;Bayliss R
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Bayliss R
影响因子：
4.3
作者：
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通讯作者：
Gee SJ
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通讯作者：
Zare, Hamed
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4.8
作者：
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通讯作者：
Cambillau, C