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Modeling and active site refinement for G protein-coupled receptors: application to the β-2 adrenergic receptor

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Abstract

It is well known that G protein-coupled receptors are prime targets for drug discovery. At the present time there is only one protein from this class that has an X-ray crystal structure, bovine rhodopsin. Crystal structures of rhodopsin have become invaluable templates for the modeling of class-A G protein-coupled receptors as they likely represent the overall topology of this family of proteins. However, because of low sequence homology within the class and the inherent mobility of integral membrane proteins, it is unlikely that this single structural template reflects the ensemble of conformations accessible for any given receptor. We have devised a procedure based upon comparative modeling that uses induced fit modeling coupled with binding site expansion. The modeling protocol enables an ensemble approach to binding mode prediction. The utility of models for β-2 adrenergic receptor will be discussed.

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Authors and Affiliations

  1. Department of Molecular Biosciences, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ, 08543-5400, USA

    Stanley R. Krystek Jr, S. Roy Kimura & Andrew J. Tebben

  2. Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, NJ, 08543-5400, USA

    Stanley R. Krystek Jr & Andrew J. Tebben

Authors
  1. Stanley R. Krystek Jr
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  2. S. Roy Kimura
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  3. Andrew J. Tebben
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Correspondence to Stanley R. Krystek Jr or Andrew J. Tebben.

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Krystek, S.R., Kimura, S.R. & Tebben, A.J. Modeling and active site refinement for G protein-coupled receptors: application to the β-2 adrenergic receptor. J Comput Aided Mol Des 20, 463–470 (2006). https://doi.org/10.1007/s10822-006-9065-z

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  • DOI: https://doi.org/10.1007/s10822-006-9065-z

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