The structure of a polyQ-anti-polyQ complex reveals binding according to a linear lattice model
The structure of a polyQ-anti-polyQ complex reveals binding according to a linear lattice model
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DOI：
10.1038/nsmb1234
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发表时间：
2007-05-01
影响因子：
16.8
通讯作者：
Bjorkman, Pamela J.
中科院分区：
文献类型：
--
作者：
Li, Pingwei;Huey-Tubman, Kathryn E.;Bjorkman, Pamela J.
亨廷顿舞蹈病和相关的神经系统疾病是由多聚谷氨酰胺（polyQ）束的扩张引起的。polyQ的结构和结合特性的线性晶格模型提出，在预聚集状态下，扩展和正常的polyQ束都是随机卷曲结构，但是扩展的polyQ重复序列包含大量的抗体或其他蛋白质识别的表位。与针对polyQ的抗体MW1结合的polyQ的晶体结构揭示了polyQ采用延伸的螺旋状结构。与线性晶格模型一致，多聚体MW1 Fv与较长的polyQ束的结合比与较短的polyQ束的结合更紧密，并且与单体Fv相比，以更高的表观亲和力结合扩展的polyQ重复序列。这些结果提示了扩增的polyQ的毒性机制和连接抗polyQ化合物以产生高亲合力治疗剂的策略。
Huntington and related neurological diseases result from expansion of a polyglutamine (polyQ) tract. The linear lattice model for the structure and binding properties of polyQ proposes that both expanded and normal polyQ tracts in the preaggregation state are random-coil structures but that an expanded polyQ repeat contains a larger number of epitopes recognized by antibodies or other proteins. The crystal structure of polyQ bound to MW1, an antibody against polyQ, reveals that polyQ adopts an extended, coil-like structure. Consistent with the linear lattice model, multimeric MW1 Fvs bind more tightly to longer than to shorter polyQ tracts and, compared with monomeric Fv, bind expanded polyQ repeats with higher apparent affinities. These results suggest a mechanism for the toxicity of expanded polyQ and a strategy to link anti-polyQ compounds to create high-avidity therapeutics.