Crystal structure of the complex of hepatocyte growth factor beta chain with Met receptor and methods of use
AssigneeGenentech, Inc.
InventorsChristian Wiesmann, Jennifer Stamos
Life of this patent
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Abstract
The disclosure provides a crystal structure of a complex of the HGF β-chain with am extracellular fragment of the Met receptor, as well as use of the crystal structure in the design, identification, and selection of ligands that modulate the Met Receptor and the interaction of HGF with the Met receptor.
Claims27
A crystal of HGF β complexed with Met comprising a human hepatocyte growth factor beta chain comprising an amino acid sequence of SEQ ID NO:1 or conservative substitutions thereof complexed with an extracellular fragment of a Met Receptor comprising an amino acid sequence of SEQ ID NO:3 or conservative substitutions thereof.
Crystalline form of a complex of HGF β-chain with an extracellular fragment of the Met Receptor.
A crystal of a 1:1 complex of the HGF β-chain with an extracellular fragment of the Met Receptor having a space group symmetry of P21212 and comprising a unit cell having the dimensions of a, b, and c, where a is about 137.1 Å, b is about 186.4 Å, and c is about 66.7 Å.
A molecule or molecular complex comprising at least a portion of the Met binding site for HGF β of a polypeptide comprising an amino acid sequence of SEQ ID NO:3 or conservative substitution thereof, wherein the binding site comprises at least one amino acid residue corresponding to residues 124 to 128, 148, 167, 190 to 192, 218, 220 to 224, 229, 230, 286, 414 or mixtures thereof, the binding site defined by a set of points having a root mean square deviation of less than about 0.70 Å from points representing the backbone atoms of the amino acids as represented by the structure coordinates listed in Table 2.
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A three-dimensional configuration of points, wherein at least a portion of the points are derived from structure coordinates representing locations of at least the backbone atoms of amino acids defining the Met binding site for HGF β.
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A machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein a machine programmed with instructions for using such data displays a graphical three-dimensional representation of at least one molecule or molecular complex comprising at least a portion of a Met binding site for HGF β, the binding site defined by a set of points having a root mean square deviation of less than about 0.05 Å from points representing the atoms of the amino acids as represented by the structure coordinates listed in Table 2.
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A molecule or molecular complex comprising at least a portion of the HGF β binding site for Met of a polypeptide comprising an amino acid sequence of SEQ ID NO:
- 1 or conservative substitution thereof, wherein the binding site comprises at least one amino acid residue corresponding to amino acid residues 513, 516, 533, 534, 537, 578, 619, 647, 649, 656, 669, 670, 673, 692, 693, 694, 695, 696, 697, 699, 702 or mixtures thereof, the binding site defined by a set of points having a root mean square deviation of less than about 0.70 Å from points representing the backbone atoms of the amino acids as represented by the structure coordinates listed in Table 2.
A machine-readable data storage medium comprising a data storage material encoded with machine-readable data, wherein a machine programmed with instructions for using such data displays a graphical three-dimensional representation of at least one molecule or molecular complex comprising at least a portion of a Met binding site on HGF β, the binding site defined by a set of points having a root mean square deviation of less than about 0.05 Å from points representing the atoms of the amino acids as represented by the structure coordinates listed in Table 2.
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Dependencies are inferred from the claim text.