6I1S

Crystal structure of the ACVR1 (ALK2) kinase in complex with FKBP12 and the inhibitor E6201

Summary for 6I1S

• Entry DOI: 10.2210/pdb6i1s/pdb
• Descriptor: Activin receptor type-1, Peptidyl-prolyl cis-trans isomerase FKBP1A, (4~{S},5~{R},6~{Z},9~{S},10~{S},12~{E})-16-(ethylamino)-4,5-dimethyl-9,10,18-tris(oxidanyl)-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione, ... (6 entities in total)
• Functional Keywords: kinase, inhibitor, alk2, acvr1, fkbp12, complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 50469.57

Authors

Williams, E.P.,Pinkas, D.M.,Fortin, J.,Newman, J.A.,Bradshaw, W.J.,Mahajan, P.,Kupinska, K.,Burgess-Brown, N.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.N. (deposition date: 2018-10-30, release date: 2019-09-11, Last modification date: 2024-01-24)

Primary citation

Fortin, J.,Tian, R.,Zarrabi, I.,Hill, G.,Williams, E.,Sanchez-Duffhues, G.,Thorikay, M.,Ramachandran, P.,Siddaway, R.,Wong, J.F.,Wu, A.,Apuzzo, L.N.,Haight, J.,You-Ten, A.,Snow, B.E.,Wakeham, A.,Goldhamer, D.J.,Schramek, D.,Bullock, A.N.,Dijke, P.T.,Hawkins, C.,Mak, T.W.
Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas.
Cancer Cell, 37:308-323.e12, 2020

PubMed Abstract: Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1 arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3b and Pik3ca to generate high-grade diffuse gliomas. Mechanistically, Acvr1 upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

PubMed: 32142668
DOI: 10.1016/j.ccell.2020.02.002

Experimental method

X-RAY DIFFRACTION (1.52 Å)