Structure of the insulin receptor ectodomain
AssigneeThe Walter and Eliza Hall Institute of Medical Research
InventorsThomas P. J. Garrett, Timothy Edward Adams, George Lovrecz, Neil Moreton McKern, Michael Colin Lawrence, Lindsay Gale Sparrow, Colin Wesley Ward, Meizhen Lou, Victor Strelstov
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Abstract
The present invention relates to the crystal structure of the insulin receptor ectodomain, to the nature of its N-linked glycans and to methods of using the crystal and related structural information to screen for and design compounds that interact with or modulate the insulin receptor and/or the closely-related insulin-like growth factor receptors or variants thereof.
Claims24
A method of identifying a compound that binds insulin receptor (IR), comprising:
- (a) obtaining a crystal comprising IR selected from the group consisting of:
- (i) an orthorhombic crystal of IR ectodomain comprising a protein consisting of residues 1-485 of SEQ ID NO:1 in space group P212121 having a cell unit dimension of a=103.86 Angstrom, b=130.24 Angstrom, and c=160.92 Angstrom, and
- (ii) an orthorhombic crystal of a complex consisting of IR-delta-beta (IRΔβ) of SEQ ID NO:15, Fab 83-7 of SEQ ID NOs:8 and 10, and Fab 83-14 of SEQ ID NOs:4 and 6 in space group C2221 having a unit cell dimension of a=123.0 Angstrom, b=319.7 Angstrom, and c=204.9 Angstrom;
- (b) determining the three-dimensional structure of the IR by X-ray diffraction to obtain the atomic coordinates of Appendix I and or II;
- (c) contacting an IR structure defined by the atomic coordinates of Appendix I and/or Appendix II, or a subset thereof with a test compound;
- and detecting an interaction between the compound and the atomic coordinates, wherein an energetically favored interaction between the test compound and the atomic coordinates is indicative of a compound that binds IR.
A method of identifying a compound that binds insulin-like growth factor 1 receptor (IGF-1R), comprising:
- (a) obtaining a crystal comprising IR selected from the group consisting of:
- (i) an orthorhombic crystal of IR ectodomain comprising a protein consisting of residues 1-485 of SEQ ID NO:1 in space group P212121 having a cell unit dimension of a=103.86 Angstrom, b=130.24 Angstrom, and c=160.92 Angstrom, and
- (ii) an orthorhombic crystal of a complex consisting of IR-delta-beta (IRΔβ) of SEQ ID NO:15, Fab 83-7 of SEQ ID NOs:8 and 10, and Fab 83-14 of SEQ ID NOs:4 and 6 in space group C2221 having a unit cell dimension of a=123.0 Angstrom, b=319.7 Angstrom, and c=204.9 Angstrom;
- (b) determining the three-dimensional structure of the IR by X-ray diffraction to obtain the atomic coordinates of Appendix I and or II;
- and
- (c) contacting an IR structure defined by the atomic coordinates of Appendix I and/or Appendix II, or a subset thereof with a test compound;
- and detecting an interaction between the compound and the atomic coordinates, wherein an energetically favored interaction between the test compound and the atomic coordinates is indicative of a compound that binds IGF-1R.
An orthorhombic crystal of IR ectodomain comprising a protein consisting of residues 1-485 of SEQ ID NO:1 in space group P212121 having a cell unit dimension of a=103.86 Angstrom, b=130.24 Angstrom, and c=160.92 Angstrom with up to 2% variation in any cell dimension.
An orthorhombic crystal of a complex consisting of IR-delta-beta (IRΔβ) of SEQ ID NO:15, Fab 83-7 of SEQ ID NOs:8 and 10, and Fab 83-14 of SEQ ID NOs:4 and 6 in space group C2221 having a unit cell dimension of a=123.0 Angstrom, b=319.7 Angstrom, and c=204.9 Angstrom with up to 2% variation in any cell dimension.
Dependencies are inferred from the claim text.