7jni

Crystal structure of the angiotensin II type 2 receptoror (AT2R) in complex with EMA401

spinqualitylabelsall models 7jni, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7jni is a 2 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: FMT, HEZ, OLA, OLC, VFD, YCM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease AGTR2_HUMAN X-linked non-syndromic intellectual disability. Function C562_ECOLX Electron-transport protein of unknown function.AGTR2_HUMAN Receptor for angiotensin II. Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation. Publication Abstract from PubMed Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or beta-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R 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. Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.,Perryman R, Renziehausen A, Shaye H, Kostagianni AD, Tsiailanis AD, Thorne T, Chatziathanasiadou MV, Sivolapenko GB, El Mubarak MA, Han GW, Zarzycka B, Katritch V, Lebon G, Lo Nigro C, Lattanzio L, Morse SV, Choi JJ, O'Neill K, Kanaki Z, Klinakis A, Crook T, Cherezov V, Tzakos AG, Syed N Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2116289119. doi:, 10.1073/pnas.2116289119. Epub 2022 Aug 2. PMID:35917342 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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