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G protein-coupled receptor structural model and a method of designing ligand binding to g protein-coupled receptor by using the structural model

a g protein-coupled receptor and structural model technology, applied in the field of structural models, can solve the problems of rhodopsin not solely providing a structural model, the role of the kink in the functioning of gpcrs remains unclear, and the nature of specific conformational changes has yet to be understood

Inactive Publication Date: 2007-01-11
SUNTORY HLDG LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036] On the other hand, TM1, TM2, and TM7 are not subjected to conformational changes because of hydrogen bonds be

Problems solved by technology

However, the role of the kink in the functioning of GPCRs still remains unclear.
For this reason, the crystal structure of rhodopsin does not solely provide a structural model for every receptor / ligand complex.
Nonetheless, the nature of specific conformational change has yet to be understood.

Method used

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  • G protein-coupled receptor structural model and a method of designing ligand binding to g protein-coupled receptor by using the structural model
  • G protein-coupled receptor structural model and a method of designing ligand binding to g protein-coupled receptor by using the structural model
  • G protein-coupled receptor structural model and a method of designing ligand binding to g protein-coupled receptor by using the structural model

Examples

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example 1

Construction of Models for Photoactivated Intermediates of Rhodopsin

[0126] Using a molecule modeling software Insight II-Discover 3 (Molecular Simulations Inc., USA), a structural model for each of the rhodopsin intermediates was generated and was optimized based an the crystal structure of rhodopsin (Palczewski et al., Science, 289, 144-167, 2000). TM3 was swung about the C α carbon of Cys110 to serve as the pivot point while the distance to TM2 was kept at 5 Å or more. The magnitude of the swing was determined by taking into consideration the interaction of TM6 with Glu247 for each of Lumi, Meta I, Meta Ib, and Meta I380 structures. Specifically, in each of Lumi, Meta I, Meta Ib, and Meta I380, Cys140 on TM3 was swung in such a manner that Cys140 is spaced form TM6 by a distance of 1.6 Å, 4.3 Å, 6.8 Å, and 9.0 Å, respectively. Furthermore, N-terminal (Glu150) of the portion of TM4 that would interfere with TM3 was swung toward TM5 about Gly174 on the C-terminal of the helix to se...

example 2

Construction of models for GPCR and GPCR / Ligand Complex

[0129] Using the structure of Meta I, Meta Ib, Meta I380, and Meta II and based on the homology among the amino acid sequences of rhodopsin and other GPCRs (FIG. 18), three-dimensional conformations for binding a full agonist, a partial agonist, an antagonist, and an inverse agonist were constructed for each of the GPCRs.

[0130] For each of the GPCRs, a receptor conformation for binding an inverse agonist was generated by using the structure of Meta I as a template. Using a homology module of Insight II, amino acid substitution was carried out, as were insertion or deletion of amino acid residues in the loop region. Using Discover 3, the conformation was optimized so that the C α carbon of the amino acids was fixed as firmly as possible.

[0131] Likewise, three-dimensional conformations for binding an antagonist, a partial agonist, and a full agonist that correspond to Meta Ib, Meta I380, and Meta II, respectively, were construc...

example 3

Construction of Structural Model for Adrenaline Receptors Bound to Antagonist

[0133] Using the structure of rhodopsin Meta Ib as a template, Meta Ib-Like structural models of antagonist-bound receptor was constructed for a panel of twelve adrenaline receptors, which form a class of G protein-coupled receptors (GPCRs).

[0134] To construct the structural model for the panel of adrenaline receptors, the amino acid sequence of rhodopsin to serve as a template was first aligned with the amino acid sequences of the panel of adrenaline receptors for which to construct the structural model Clustal W was used as the alignment program (Thompson et al., Nucleic Acids Research, 22:4673-4680(1994)). The analysis revealed that while the amino acid sequences showed a relatively low homology to one another, the transmembrane regions, which include conserved hydrophobic residues and sequence motifs, are aligned at a relatively high homology, and the less conserved loop regions tend to include abnorm...

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Abstract

The present invention provides a method for constructing a structural model of a complex that a G protein-coupled protein receptor forms with a ligand capable of binding the G protein-coupled receptor and a three-dimensional structural model of an activated intermediate in the structural model of the complex. The present invention also provides a method for identifying, screening for, searching for, evaluating, or designing a ligand capable of binding a GPCR by using the three-dimensional model. In one specific method by the present invention, a three-dimensional structural model of a photoactivated intermediate of rhodopsin is constructed by using a molecule modeling software and by using the three-dimensional structural coordinate of the crystal structure of rhodopsin in such a manner that amino acid residues highly conserved among GPCRs are taken into consideration. The three-dimensional stractural model of the photoactivated intermediate of rhodopsin is subsequently used to construct structural models of activated intermediates of other GPCRs. The present invention further provides a method for identifying, screening for, searching for, evaluating, or designing a ligand that binds a GPCR to act as an agonist or an antagonist. This method employs the three-dimensional structural model constructed by the above-described method.

Description

TECHNICAL FIELD [0001] The present invention relates to a structural model for receptor / ligand complexes of G protein-coupled receptors (which may be referred to simply as ‘GPCRs,’ hereinafter) and ligands capable of binding to G protein-coupled receptors. It also relates to a method for creating a three-dimensional structural model for activated intermediates of G protein-coupled receptors in the structural model for the receptor / ligand complexes, as well as to structural models of the complexes or the activated intermediates of G protein-coupled receptors obtained by this method. The present invention further relates to a three-dimensional coordinate for determining these structural models. [0002] The present invention further relates to a method for using the three-dimensional structural model of G protein-coupled receptors or a method for using the three-dimensional coordinates for determining the structural model in identifying, screening for, searching for, evaluating, and des...

Claims

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Application Information

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IPC IPC(8): G06F19/00G01N33/48G01N33/50G16B5/00C07K14/72G01N33/566G01N33/68G16B15/30
CPCC07K14/723C07K2299/00G06F19/12G01N33/6803G06F19/16G01N33/566G16B15/00G16B15/30G16B5/00
Inventor ISHIGURO, MASAJI
Owner SUNTORY HLDG LTD
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