Crystallization of c-KIT tyrosine kinase leading to autoinhibited crystal structure

1. A composition comprising a c-KIT tyrosine kinase (c-KIT) protein in crystalline form wherein the protein consists of SEQ ID NO:3, and wherein the protein crystal has a crystal lattice in a P2 1 2 1 2 space group and unit cell dimensions, +/−5%, of a=44.489 Å b=77.277 Å and c=94.701 Å, α=β=γ=90.

2. A composition according to claim 1 wherein the protein crystal diffracts X-rays for a determination of structure coordinates to a resolution less than 3.0 Angstroms.

3. A method for forming a crystal of a c-KIT tyrosine kinase (c-KIT) protein comprising:

forming a crystallization volume comprising a precipitant solution and a protein that consists of SEQ ID NO:3, and wherein the protein crystal has a crystal lattice in a P2 1 2 1 2 space group and unit cell dimensions, +/−5%, of a=44.489 Å b=77.277 Å and c=94.701 Å, α=β=γ=90; and

storing the crystallization volume under conditions suitable for crystal formation until a crystal is formed.

4. A method according to claim 3 wherein the protein crystal diffracts X-rays for a determination of structure coordinates to a resolution less than 3.0 Angstroms.

5. A non-crystalline protein consisting of SEQ ID NO:3.

6. An isolated noncrystalline protein consisting of residues 544-693 and 753-935 of SEQ ID NO:1.

7. The protein according to claim 6 where the protein is expressed from a nucleic acid molecule that consists of SEQ ID NO:2.

8. A non-crystalline protein consisting of amino acids 544-693 and 753-935 of SEQ ID NO:1.

9. An isolated non-crystalline protein consisting of SEQ ID NO:3.

10. A method for obtaining a three dimensional structure of a c-KIT tyrosine kinase (c-KIT) protein comprising the steps of:

(a) obtaining a crystal of a protein whose sequence consists of SEQ ID NO:3, wherein the protein crystal has a crystal lattice in a P2 1 2 1 2 space group and unit cell dimensions, +/−5%, of a=44.489 Å b=77.277 Å and c=94.701 Å, α=β=γ=90;

(b) using the crystal obtained in step (a) to obtain an x-ray diffraction pattern; and

(c) solving the three dimensional structure of the protein from the diffraction pattern obtained in step (b), thereby obtaining the three dimensional structure of the protein.

11. A method for identifying a compound that binds to a c-KIT tyrosine kinase (c-KIT) protein comprising the steps of:

(a) obtaining a crystal of a protein whose sequence consists of SEQ ID NO:3, wherein the protein crystal has a crystal lattice in a P2 1 2 1 2 space group and unit cell dimensions, +/−5%, of a=44.489 Å b=77.277 Å and c=94.701 Å, α=β=γ=90;

(b) using the crystal obtained in step (a) to obtain an x-ray diffraction pattern;

(c) solving the three dimensional structure of the protein from the diffraction pattern obtained in step (b), thereby obtaining the three dimensional structure of the protein; and

(d) identifying one or more compounds that binds to the protein based on the three dimensional structure.

12. The method according to claim 11 , further comprising the step of:

contacting one or more compounds identified in step (d) with the protein whose sequence consists of SEQ ID NO:3.

13. The method according to claim 12 , further comprising the step of:

measuring an activity of the protein whose sequence consists of SEQ ID NO:3, when the protein is contacted with the one or more compounds.

14. The method according to claim 13 , further comprising the step of:

comparing activities of the protein whose sequence consists of SEQ ID NO:3, when the protein is in the presence of and in the absence of the one or more compounds.

15. The method according to claim 11 , further comprising the steps of:

contacting one or more compounds identified in step (d) with a cell that expresses a protein whose sequence consists of SEQ ID NO:3; and

detecting whether a phenotype of the cell changes when the one or more compounds are present.