| US 7,593,820 B2 | ||
| Crystal structure of human Janus Kinase 2 (JAK2) and uses thereof | ||
| Andrew Frederick Wilks, South Yarra (Australia); Christopher John Burns, Seddon (Australia); Emmanuelle Fantino, Elwood (Australia); Isabelle Lucet, Glen Waverley (Australia); Jamie Rossjohn, Carnegie (Australia); and Michelle Leanne Styles, Golden Square (Australia) | ||
| Assigned to Cytopia Research Pty Ltd, Richmond (Australia) | ||
| Filed on Oct. 11, 2005, as Appl. No. 11/248,478. | ||
| Claims priority of application No. 2005902420 (AU), filed on May 12, 2005. | ||
| Prior Publication US 2007/0128709 A1, Jun. 07, 2007 | ||
| Int. Cl. G01N 31/00 (2006.01); C12N 9/12 (2006.01); G06G 7/58 (2006.01) | ||
| U.S. Cl. 702—27 [435/194; 703/11] | 5 Claims |
| 1. A method of selecting or designing a candidate compound or compounds that interact with human Janus Kinase 2 (JAK2) and
modulate human JAK2 kinase activity, the method comprising the steps of:
(a) generating a three-dimensional model of the kinase domain of said human JAK2 defined by the three-dimensional structural
coordinates according to Appendix I, wherein said kinase domain consists of SEQ ID NO: 7 and/or SEQ ID NO: 8;
(b) selecting the region that form the ATP binding pocket and sugar binding pocket from the three-dimensional model in (a)
which comprise amino acid acids Glu930, Leu932, Asp939, Ser936, Leu855, Arg980, Gly993, Asp994, Ala880, Val911, Leu983, Gly935,
Met929 and Tyr931, Gln853, Gly856, Lys857, Gly858, Asn859, Phe860, Gly861, Ser862, Va1863, Met865, Va1878, Lys882, Glu898,
Leu902, Tyr913, Leu927, Pro933, Tyr934, Asn981, 11e982, Phe995, Gly996, including the sugar binding pocket amino acids Arg938,
Ala978, Thr979 to generate a three-dimensional target; wherein the numbering of human JAK 2 is shown in either sequence A
(SEQ ID NO: 7) or sequence B (SEQ ID NO: 8) of Appendix 1,
(c) assessing the stereochemical complementarity between the candidate compound(s) and said region; and
(d) testing the compound in vitro or in vivo for its capacity to modulate the kinase activity of human JAK2;
wherein the structural coordinates of the amino acids and water molecules in (a) and/or (b) have a root mean square deviation
of no more than 1.0 Å from the backbone atoms in the amino acids shown in Appendix 1.
|