7JNI
Crystal structure of the angiotensin II type 2 receptoror (AT2R) in complex with EMA401
Summary for 7JNI
| Entry DOI | 10.2210/pdb7jni/pdb |
| Descriptor | Soluble cytochrome b562,Type-2 angiotensin II receptor, Olodanrigan, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (7 entities in total) |
| Functional Keywords | angiotensin ii type 2 receptor, at2r, ema401, pd-126055, g protein-coupled receptor, gpcr, bril fusion, glioblastoma, gbm, membrane protein, lcp |
| Biological source | Escherichia coli More |
| Total number of polymer chains | 2 |
| Total formula weight | 96734.20 |
| Authors | Cherezov, V.,Shaye, H.,Han, G.W. (deposition date: 2020-08-04, release date: 2022-02-09, Last modification date: 2023-10-18) |
| Primary citation | Perryman, R.,Renziehausen, A.,Shaye, H.,Kostagianni, A.D.,Tsiailanis, A.D.,Thorne, T.,Chatziathanasiadou, M.V.,Sivolapenko, G.B.,El Mubarak, M.A.,Han, G.W.,Zarzycka, B.,Katritch, V.,Lebon, G.,Lo Nigro, C.,Lattanzio, L.,Morse, S.V.,Choi, J.J.,O'Neill, K.,Kanaki, Z.,Klinakis, A.,Crook, T.,Cherezov, V.,Tzakos, A.G.,Syed, N. Inhibition of the angiotensin II type 2 receptor AT 2 R is a novel therapeutic strategy for glioblastoma. Proc.Natl.Acad.Sci.USA, 119:e2116289119-e2116289119, 2022 Cited by PubMed Abstract: Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (ATR) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through ATR. We repurposed EMA401, an ATR antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of ATR-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of ATR bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or β-arrestin recruitment. The architecture and interactions of EMA401 in ATR differ drastically from complexes of ATR with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2-tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM. PubMed: 35917342DOI: 10.1073/pnas.2116289119 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3 Å) |
Structure validation
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