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Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1).
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; Lipovsek, Dasa; Sheriff, Steven.
  • Lau WL; Biologics Discovery, Bristol-Myers Squibb Research and Development, 100 Binney Street, Cambridge, MA 02142, USA.
  • Pearce B; Molecular Structure and Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
  • Malakian H; Biologics Discovery, Bristol-Myers Squibb Research and Development, 100 Binney Street, Cambridge, MA 02142, USA.
  • Rodrigo I; Protein Science, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Xie D; Protein Science, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Gao M; Protein Science, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Marsilio F; Protein Science, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Chang C; Molecular Structure and Design, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Ruzanov M; Molecular Structure and Design, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Muckelbauer JK; Molecular Structure and Design, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Newitt JA; Protein Science, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
  • Lipovsek D; Biologics Discovery, Bristol-Myers Squibb Research and Development, 100 Binney Street, Cambridge, MA 02142, USA.
  • Sheriff S; Molecular Structure and Design, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
Acta Crystallogr F Struct Biol Commun ; 77(Pt 1): 22-28, 2021 Jan 01.
Article en En | MEDLINE | ID: mdl-33439152
ABSTRACT
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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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ingeniería de Proteínas / Proteínas Serina-Treonina Quinasas Límite: Humans Idioma: En Año: 2021 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ingeniería de Proteínas / Proteínas Serina-Treonina Quinasas Límite: Humans Idioma: En Año: 2021 Tipo del documento: Article