Homology modeling of class a G protein-coupled receptors.
Homology modeling of class a G protein-coupled receptors.
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DOI：
10.1007/978-1-61779-588-6_11
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Costanzi, Stefano
中科院分区：
文献类型：
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作者：
Costanzi, Stefano
G蛋白偶联受体（gpcr）是一个大的膜结合信号蛋白超家族，具有很大的制药价值。由于实验阐明的结构仅适用于非常有限数量的受体，因此同源性建模已成为构建GPCR模型的一种广泛技术，旨在研究受体的结构-功能关系，并有助于发现和开发能够调节其活性的配体。通过本章，说明了最大的一类gpcr（称为A类或视紫红质家族）蛇形结构域的同源模型构建所涉及的各个方面。特别是，本章提供了关于GPCR建模的一些最关键方面的建议，指导方针和批判性思想，包括：候选模板的收集和基于结构的序列比对；将查询受体的跨膜螺旋与候选模板的相应结构域进行鉴定和比对；一个或多个模板受体的选择；选择同源或重新建模，以构建特定的细胞外和细胞内结构域；三维模型的构建，特别考虑细胞外区域、二硫桥和螺旋腔；通过受控虚拟筛选实验对模型进行了验证。
G protein-coupled receptors (GPCRs) are a large superfamily of membrane bound signaling proteins that hold great pharmaceutical interest. Since experimentally elucidated structures are available only for a very limited number of receptors, homology modeling has become a widespread technique for the construction of GPCR models intended to study the structure-function relationships of the receptors and aid the discovery and development of ligands capable of modulating their activity. Through this chapter, various aspects involved in the constructions of homology models of the serpentine domain of the largest class of GPCRs, known as class A or rhodopsin family, are illustrated. In particular, the chapter provides suggestions, guidelines and critical thoughts on some of the most crucial aspect of GPCR modeling, including: collection of candidate templates and a structure-based alignment of their sequences; identification and alignment of the transmembrane helices of the query receptor to the corresponding domains of the candidate templates; selection of one or more templates receptor; election of homology or de novo modeling for the construction of specific extracellular and intracellular domains; construction of the three-dimensional models, with special consideration to extracellular regions, disulfide bridges, and interhelical cavity; validation of the models through controlled virtual screening experiments.