9S9T
Structure of human PKCBeta Kinase domain with Ruboxistaurin, D427N mutant
Summary for 9S9T
| Entry DOI | 10.2210/pdb9s9t/pdb |
| Descriptor | Isoform Beta-II of Protein kinase C beta type, (9R)-9-[(DIMETHYLAMINO)METHYL]-6,7,10,11-TETRAHYDRO-9H,18H-5,21:12,17-DIMETHENODIBENZO[E,K]PYRROLO[3,4-H][1,4,13]OXADIA ZACYCLOHEXADECINE-18,20-DIONE (2 entities in total) |
| Functional Keywords | kinase, inhibitor, mutant, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41219.87 |
| Authors | Briggs, D.C.,Parker, P.J.,McDonald, N.Q.,Brown, S.J. (deposition date: 2025-08-06, release date: 2025-11-05, Last modification date: 2025-12-24) |
| Primary citation | Brown, S.J.,Briggs, D.C.,Costello, P.,Yaguchi, H.,Bangham, C.R.,Parker, P.J.,McDonald, N.Q. Penetrant PKC beta mutation in ATLL displays a mixed gain-of-function. Biochem.J., 482:1659-1675, 2025 Cited by PubMed Abstract: Mutations in the T-cell receptor signalling pathway have been identified in patients with adult T-cell leukaemia/lymphoma (ATLL) and one of the most frequently observed targets of these mutations is protein kinase C beta (PKCβ). Here, we have characterised the most frequent mutation in PKCβ (D427N), addressing the issue of gain/loss of function, neomorphic change and assessing the impact of mutation in vivo, in cells, biochemically and structurally. It is concluded that this mutation is a gain-of-function, activating mutation that confers an altered substrate specificity on this protein kinase. In a constitutive knock-in mouse model, this activated allele induces splenomegaly associated with extramedullary haematopoiesis. Pharmacologically, the D427N mutant protein displays poor sensitivity to established PKCβ inhibitors, necessitating the development of bespoke therapeutics for any ATLL intervention through this target. Such efforts could be guided by the availability of the D427N mutant-ruboxistaurin structure presented here. PubMed: 41091072DOI: 10.1042/BCJ20253384 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.425 Å) |
Structure validation
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