5h7o

Crystal structure of DJ-101 in complex with tubulin protein

spinqualitylabelsall models 5h7o, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5h7o is a 6 chain structure with sequence from Bos taurus, Gallus gallus, Rattus norvegicus and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: 7Q7, ACP, CA, GDP, GOL, GTP, MES, MG 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. Publication Abstract from PubMed Antimitotics that target tubulin are among the most useful chemotherapeutic drugs, but their clinical activity is often limited by the development of multidrug resistance. We recently discovered the novel small molecule DJ101 as a potent and metabolically stable tubulin inhibitor that can circumvent the drug efflux pumps responsible for multidrug resistance of existing tubulin inhibitors. In this study, we determined the mechanism of action of this drug. The basis for its activity was illuminated by solving the crystal structure of DJ101 in complex with tubulin at a resolution of 2.8A. Investigations of the potency of DJ101 in a panel of human metastatic melanoma cell lines harboring major clinically relevant mutations defined IC50 values of 7-10 nM. In cells, DJ101 disrupted microtubule networks, suppressed anchorage-dependent melanoma colony formation and impaired cancer cell migration. In melanoma-bearing mice, DJ101 administration inhibited tumor growth and reduced lung metastasis in the absence of observable toxicity. DJ101 also completely inhibited tumor growth in a paclitaxel-resistant xenograft mouse model of human prostate cancer (PC-3/TxR), where paclitaxel was minimally effective. Our findings offer preclinical proof of concept for the continued development of DJ101 as a next-generation tubulin inhibitor for cancer therapy. A potent, metabolically stable tubulin inhibitor targets the colchicine binding site and overcomes taxane resistance.,Arnst KE, Wang Y, Hwang DJ, Xue Y, Costello T, Hamilton D, Chen Q, Yang J, Park F, Dalton JT, Miller DD, Li W Cancer Res. 2017 Nov 27. pii: 0008-5472.CAN-17-0577. doi:, 10.1158/0008-5472.CAN-17-0577. PMID:29180476 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Stathmin-4 3D structures Tubulin 3D Structures

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