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Prediction of structure, function, and spectroscopic properties of G-protein-coupled receptors: Methods and applications.

机译：G蛋白偶联受体的结构，功能和光谱性质的预测：方法和应用。

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摘要

G-protein-coupled receptors are of great pharmaceutical interest, comprising the majority of targets for currently marketed drugs. The theme of my thesis is the development of the structure prediction method, MembStruk, for the superfamily of G-protein-coupled receptors. The first part of this thesis focuses on the methods and their validation. There are several steps involved in MembStruk that are detailed and tested for membrane proteins with known structures in the first few chapters (Chapters 2--6). Specifically, the first principles methods for predicting the transmembrane helical ranges and the helix hydrophobic centers are tested. The program for predicting the transmembrane helical ranges, TM2ndS, ranks in the top two when comparing performance with other top prediction methods. And because it is based on general principles, it can be applied robustly for membrane protein families for which little structural information is available. The simulation of the EC-II closing is also tested on bovine rhodopsin. The use of the MembStruk method on bovine rhodopsin as a validation case is presented in detail (Chapter 2). The large majority (71%) of the residues involved in binding in rhodopsin are predicted and the protein structure itself is 2.84 A coordinate root mean square error in the transmembrane main chain atoms from the crystal structure.; The second part of the thesis discusses applications on various G-protein-coupled receptor systems. The application of the MembStruk method to other peptide chemokine G-protein-coupled receptors like CCR1 and CCR5 is discussed in Chapter 9. The fundamental scientific problems of G-protein-coupled receptor modulation of absorption and relaxation properties of a bound chromophore (retinal) are addressed and results are presented for the predictions of these properties.; The prediction of structure and function of G-protein-coupled receptors would allow for structure-based drug design and a rational approach to reducing drug cross-reactivity across receptor families.
机译：G蛋白偶联受体具有巨大的药学意义，包括目前市售药物的大多数靶标。本文的主题是为G蛋白偶联受体超家族开发结构预测方法MembStruk。本文的第一部分着眼于方法及其验证。在前几章中，MembStruk涉及多个步骤，详细介绍了具有已知结构的膜蛋白并对其进行了测试（第2--6章）。具体而言，测试了用于预测跨膜螺旋范围和螺旋疏水中心的第一原理方法。将性能与其他顶级预测方法进行比较时，用于预测跨膜螺旋范围的程序TM2ndS排名前两名。而且由于它是基于一般原理的，因此可以牢固地应用于几乎没有结构信息的膜蛋白家族。还对牛视紫红质测试了EC-II关闭的模拟。详细介绍了将MembStruk方法用于牛视紫红质的验证案例（第2章）。在视紫红质中，参与结合的大部分残基（71％）可以预测，蛋白质结构本身为2.84 A晶体结构的跨膜主链原子的均方根误差。本文的第二部分讨论了在各种G蛋白偶联受体系统上的应用。第9章讨论了MembStruk方法在其他肽趋化因子G蛋白偶联受体（如CCR1和CCR5）中的应用。G蛋白偶联受体调节结合发色团（视网膜）的吸收和弛豫特性的基本科学问题。解决这些问题并给出结果以预测这些性质。 G蛋白偶联受体的结构和功能的预测将允许基于结构的药物设计和合理的方法来减少跨受体家族的药物交叉反应性。

著录项

  • 作者

    Trabanino, Rene.;

  • 作者单位

    California Institute of Technology.;

  • 授予单位 California Institute of Technology.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 329 p.
  • 总页数 329
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

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