气候变化领域集成服务门户(CCPortal): Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site

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DOI	10.1073/pnas.2021847118
	Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site
	Matthew S.; Chen Q.-Y.; Ratnayake R.; Fermaintt C.S.; Lucena-Agell D.; Bonato F.; Prota A.E.; Lim S.T.; Wang X.; Díaz J.F.; Risinger A.L.; Paul V.J.; Oliva M.Á.; Luesch H.
发表日期	2021
ISSN	00278424
卷号	118 期号:9
英文摘要	Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin−GB1 complex. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cyanobacteria; Marine natural product; Microtubules; Total synthesis; Tubulin
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180501
作者单位	Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, United States; Center for Natural Products, Drug Discovery and Development, University of Florida, Gainesville, FL 32610, United States; Department of Pharmacology, University of Texas, Health Science Center at San Antonio, San Antonio, TX 78229, United States; Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Madrid, 28040, Spain; Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, Villigen, CH-5232, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University636921, Singapore; Smithsonian Marine Station, Fort Pierce, FL 34949, United States
推荐引用方式 GB/T 7714	Matthew S.,Chen Q.-Y.,Ratnayake R.,et al. Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site[J],2021,118(9).
APA	Matthew S..,Chen Q.-Y..,Ratnayake R..,Fermaintt C.S..,Lucena-Agell D..,...&Luesch H..(2021).Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site.Proceedings of the National Academy of Sciences of the United States of America,118(9).
MLA	Matthew S.,et al."Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site".Proceedings of the National Academy of Sciences of the United States of America 118.9(2021).