6brf | pdb_00006brf

Tubulin-RB3_SLD-TTL in complex with heterocyclic pyrimidine compound 4b

spinqualitylabelsall models 6brf, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6brf is a 6 chain structure with sequence from Chick, Human and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACP, CA, E44, GDP, GTP, MES, MG Related: 6br1 Gene: STMN4 (HUMAN), TTL (CHICK) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TBA1B_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [STMN4_HUMAN] Exhibits microtubule-destabilizing activity. [A0A287AGU7_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.[RuleBase:RU000352][SAAS:SAAS00031082] Publication Abstract from PubMed We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions but also contrast the previously published proposed binding mode. Compounds 4a and 6a significantly inhibited tumor growth in an A375 melanoma xenograft model and were accompanied by elevated levels of apoptosis and disruption of tumor vasculature. Finally, we demonstrated that compound 4a significantly overcame clinically relevant multidrug resistance in a paclitaxel resistant PC-3/TxR prostate cancer xenograft model. Collectively, these studies provide preclinical and structural proof of concept to support the continued development of this scaffold as a new generation of tubulin inhibitors. Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy.,Banerjee S, Arnst KE, Wang Y, Kumar G, Deng S, Yang L, Li GB, Yang J, White SW, Li W, Miller DD J Med Chem. 2018 Feb 22;61(4):1704-1718. doi: 10.1021/acs.jmedchem.7b01858. Epub , 2018 Feb 12. PMID:29406710 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Stathmin Tubulin Tubulin tyrosine ligase

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