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7kac

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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

Structural highlights

7kac is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

M4K1_HUMAN Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.^[1] ^[2]

Publication Abstract from PubMed

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.

Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1).,Lau WL, Pearce B, Malakian H, Rodrigo I, Xie D, Gao M, Marsilio F, Chang C, Ruzanov M, Muckelbauer JK, Newitt JA, Lipovsek D, Sheriff S Acta Crystallogr F Struct Biol Commun. 2021 Jan 1;77(Pt 1):22-28. doi:, 10.1107/S2053230X20016015. Epub 2020 Dec 22. PMID:33439152^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang H, Chen Y, Lin P, Li L, Zhou G, Liu G, Logsdon C, Jin J, Abbruzzese JL, Tan TH, Wang H. The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1. J Biol Chem. 2014 Feb 14;289(7):4009-17. doi: 10.1074/jbc.M113.520106. Epub 2013 , Dec 20. PMID:24362026 doi:http://dx.doi.org/10.1074/jbc.M113.520106
↑ Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev. 1996 Sep 15;10(18):2251-64. PMID:8824585
↑ Lau WL, Pearce B, Malakian H, Rodrigo I, Xie D, Gao M, Marsilio F, Chang C, Ruzanov M, Muckelbauer JK, Newitt JA, Lipovsek D, Sheriff S. Using yeast surface display to engineer a soluble and crystallizable construct of hematopoietic progenitor kinase 1 (HPK1). Acta Crystallogr F Struct Biol Commun. 2021 Jan 1;77(Pt 1):22-28. doi:, 10.1107/S2053230X20016015. Epub 2020 Dec 22. PMID:33439152 doi:http://dx.doi.org/10.1107/S2053230X20016015