Premium
Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1)
Author(s) -
Lau Wai L.,
Pearce Bradley,
Malakian Heather,
Rodrigo Iyoncy,
Xie Dianlin,
Gao Mian,
Marsilio Frank,
Chang Chiehying,
Ruzanov Max,
Muckelbauer Jodi K.,
Newitt John A.,
Lipovšek Daša,
Sheriff Steven
Publication year - 2021
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 37
ISSN - 2053-230X
DOI - 10.1107/s2053230x20016015
Subject(s) - protein kinase domain , yeast , microbiology and biotechnology , kinase , haematopoiesis , biology , computational biology , chemistry , biochemistry , stem cell , mutant , gene
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.