7KAC

Crystal structure of HPK1 (MAP4K1) kinase in complex with 5-{[4-{[(1S)-2-HYDROXY-1-PHENYLETHYL]AMINO}-5-(1,3,4-OXADIAZOL-2-YL)PYRIMIDIN-2-YL]AMINO}-3,3-DIMETHYL-2-BENZOFURAN-1(3H)-ONE

Summary for 7KAC

• Entry DOI: 10.2210/pdb7kac/pdb
• Descriptor: Isoform 2 of Mitogen-activated protein kinase kinase kinase kinase 1, 5-{[4-{[(1S)-2-hydroxy-1-phenylethyl]amino}-5-(1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]amino}-3,3-dimethyl-2-benzofuran-1(3H)-one (3 entities in total)
• Functional Keywords: kinase, map4k1, hpk1, serine/threonine-protein kinase, hematopoietic progenitor kinase, mapk/erk kinase kinase kinase 1, mek kinase kinase 1, mekkk1, nucleotide-binding, phosphoprotein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 77024.58

Authors

Sheriff, S. (deposition date: 2020-09-30, release date: 2021-01-13, Last modification date: 2023-10-18)

Primary citation

Lau, W.L.,Pearce, B.,Malakian, H.,Rodrigo, I.,Xie, D.,Gao, M.,Marsilio, F.,Chang, C.,Ruzanov, M.,Muckelbauer, J.K.,Newitt, J.A.,Lipovsek, D.,Sheriff, S.
Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1).
Acta Crystallogr.,Sect.F, 77:22-28, 2021

PubMed 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.

PubMed: 33439152
DOI: 10.1107/S2053230X20016015

Experimental method

X-RAY DIFFRACTION (1.85 Å)