Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from nanovolume crystallography.
Protein kinases are important drug targets in human cancers, inflammation, and metabolic diseases. This report presents the structures of kinase domains for three cancer-associated protein kinases: ephrin receptor A2 (EphA2), focal adhesion kinase (FAK), and Aurora-A. The expression profiles of EphA2, FAK, and Aurora-A in carcinomas suggest that inhibitors of these kinases may have inherent potential as therapeutic agents. The structures were determined from crystals grown in nanovolume droplets, which produced high-resolution diffraction data at 1.7, 1.9, and 2.3 A for FAK, Aurora-A, and EphA2, respectively. The FAK and Aurora-A structures are the first determined within two unique subfamilies of human kinases, and all three structures provide new insights into kinase regulation and the design of selective inhibitors.
Nowakowski
Jacek
J
Syrrx, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA. jacek.nowakoski@syrrx.com
Cronin
Ciarán N
CN
McRee
Duncan E
DE
Knuth
Mark W
MW
Nelson
Christian G
CG
Pavletich
Nikola P
NP
Rogers
Joe
J
Sang
Bi-Ching
BC
Scheibe
Daniel N
DN
Swanson
Ronald V
RV
Thompson
Devon A
DA
D000595:Amino Acid Sequence; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D036103:Nanotechnology; D009369:Neoplasms / Q000201:enzymology*; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D036104:Receptor, EphA2 / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D029867:Xenopus Proteins
D018797:Cell Cycle Proteins; D029867:Xenopus Proteins; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D036104:Receptor, EphA2; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C112134:AURKA protein, Xenopus; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases