期刊
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
卷 77, 期 -, 页码 22-28出版社
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S2053230X20016015
关键词
hematopoietic progenitor kinase 1; HPK1; homology modeling; yeast surface display; crystallizability
This study utilized yeast surface display to select HPK1 kinase-domain variants with improved expression level and solubility, leading to successful crystallization and valuable insights for drug design.
Hematopoietic progenitor kinase 1 (HPK1) is an intracellular kinase that plays an important role in modulating tumor immune response and thus is an attractive target for drug discovery. Crystallization of the wild-type HPK1 kinase domain has been hampered by poor expression in recombinant systems and poor solubility. In this study, yeast surface display was applied to a library of HPK1 kinase-domain variants in order to select variants with an improved expression level and solubility. The HPK1 variant with the most improved properties contained two mutations, crystallized readily in complex with several small-molecule inhibitors and provided valuable insight to guide structure-based drug design. This work exemplifies the benefit of yeast surface display towards engineering crystallizable proteins and thus enabling structure-based drug discovery.
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