Crystal structure of the complex of hepatocyte growth factor beta chain with met receptor and methods of use

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.

1 - 33 . (canceled) 
     
     
         34 . A computer-implemented method for causing a display of a graphical three-dimensional representation of the structure of a portion of a crystal of a 1:1 complex of an extracellular fragment of a Met Receptor or structural homolog thereof with an HGF β-chain or structural homolog thereof, wherein the method comprises:
 causing said display of said graphical three-dimensional representation by a computer system programmed with instructions for transforming structure coordinates into said graphical three-dimensional representation of said structure and for displaying said graphical three-dimensional representation, 
 wherein said graphical three-dimensional representation is generated by transforming said structure coordinates into said graphical three-dimensional representation of said structure, 
 wherein said structure coordinates comprise structure coordinates of the backbone atoms of the portion of the crystal, 
 wherein the portion of the crystal comprises one or more of: the Met Receptor binding site for HGF β-chain, the Met Receptor blades of the propeller, the Met Receptor PSI domain, the Met Receptor Sema domain, and the HGF β-chain binding site for Met Receptor, and 
 wherein the crystal has the space group symmetry P2 1 2 1 2. 
 
     
     
         35 . The computer-implemented method of  claim 34 , wherein the portion of the crystal comprises the amino acids defining the Met Receptor binding site for HGF β-chain. 
     
     
         36 . The computer-implemented method of  claim 34 , wherein the portion of the crystal comprises the amino acids defining the Met Receptor structural binding site for HGF β-chain. 
     
     
         37 . The computer-implemented method of  claim 34 , wherein the portion of the crystal comprises the amino acids defining the Met Receptor functional binding site for HGF β-chain. 
     
     
         38 . The computer-implemented method of  claim 34 , wherein the portion of the crystal comprises the amino acids defining the Met Receptor blades of the propeller. 
     
     
         39 . The computer-implemented method of  claim 34 , wherein the portion of the crystal comprises the amino acids defining the Met Receptor PSI domain. 
     
     
         40 . The computer-implemented method of  claim 34 , wherein the portion of the crystal comprises the amino acids defining the Met Receptor Sema domain. 
     
     
         41 . The computer-implemented method of  claim 34 , wherein the portion of the crystal comprises the amino acids defining the HGF β-chain binding site for Met Receptor. 
     
     
         42 . The computer-implemented method of  claim 34 , wherein the structure coordinates of the backbone atoms of the portion of the crystal comprise Met Receptor structure coordinates, and wherein the Met Receptor comprises a polypeptide having an amino acid sequence of SEQ ID NO:3 or conservative substitutions thereof. 
     
     
         43 . The computer-implemented method of  claim 34 , wherein the structure coordinates are defined in Table 2. 
     
     
         44 . The computer-implemented method of  claim 34 , wherein the structure coordinates comprise the structure coordinates of the backbone atoms of the amino acid residues corresponding to positions 124-128, 148, 167, 190-192, 218, 220-224, 227, 229-230, 286, and 414 of SEQ ID NO:3. 
     
     
         45 . The computer-implemented method of  claim 34 , wherein the structure coordinates comprise the structure coordinates of the backbone atoms of the amino acid residues corresponding to positions 124-128, 148, 167, 190-192, 218, 220-223, 229-230, 286, and 414 of
 SEQ ID NO:3.   
     
     
         46 . The computer-implemented method of  claim 34 , wherein the structure coordinates comprise the structure coordinates of the backbone atoms of the amino acid residues corresponding to positions 125-128, 148, 168, 191-192, 218, 221 and 223-224 of SEQ ID NO:3. 
     
     
         47 . The computer-implemented method of  claim 34 , wherein the structure coordinates comprise the structure coordinates of the backbone atoms of the amino acid residues whose backbone atoms are situated within a 5 Å sphere centered on the coordinates representing the alpha carbon of the amino acid corresponding to position 221 of SEQ ID NO:3. 
     
     
         48 . The computer-implemented method of  claim 34 , wherein the HGF β-chain or structural homolog thereof is a HGF β-chain. 
     
     
         49 . The computer-implemented method of  claim 34 , wherein the structure coordinates are determined by homology modeling.