Approaches to the Molecular Modeling of 7‐Transmembrane Helical Receptors

Frank E. Blaney1

1 GlaxoSmithKline, NFSP (North), Harlow, Essex
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 9.8
DOI:  10.1002/0471141755.ph0908s35
Online Posting Date:  December, 2006
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7‐Transmembrane helical receptors (7TMs) represent the single most important class of target for drug therapy; therefore, a great deal of effort has gone into computational studies of their structures. Historically, these were based on low resolution electron diffraction data, together with the use of computational methods such as multiple sequence alignments, distance geometry, and molecular mechanics calculations. In the year 2000 the situation changed when the first crystal structure of a 7TM, was published. It was then possible to use the homology modeling techniques to generate more accurate models of these proteins. This unit reviews the modeling of 7TMs and describes in detail how homology modeling can be used to build a structure of the 5‐HT2a receptor. Special attention is given to the initial sequence alignment, the most important step in the process. Use of automatic alignment programs often produces incorrect results, and manual intervention is necessary before proceeding further.

Keywords: GPCR; homology modeling; sequence alignment; molecular mechanics; rhodopsin; CHARMm

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Table of Contents

  • Theory Behind Methods Used in Fifth Generation Models
  • Building A 5‐HT2A Model Based on the Bovine Rhodopsin Crystal Structure
  • Summary and Further Considerations
  • Appendix: CHARMm Scripts
  • Literature Cited
  • Figures
  • Tables
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Internet Resources
  The full text of an article about molecular modeling of GPCRs by G. Vriend in 1995.
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