Structural insights into the interaction of three Y- shaped ligands with PI3Kα
文献类型：期刊论文
| 作者 | Zhou, Qingtong8; Liu, Xiao8; Neri, Dario1,7; Li, Wenxin8; Favalli, Nicholas1,7; Bassi, Gabriele1,7; Yang, Su6,7; Yang, Dehua5 ; Vogt, Peter K.6; Wang, Ming-Wei2,3,4,8
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| 刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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| 出版日期 | 2023-08-22 |
| 卷号 | 120期号:34页码:9 |
| ISSN号 | 0027-8424 |
| 关键词 | phosphoinositide 3-kinase drug target ligand binding pocket chemical scaffold |
| DOI | 10.1073/pnas.2304071120 |
| 通讯作者 | Yang, Dehua(dhyang@simm.ac.cn) ; Vogt, Peter K.(pkvogt@scripps.edu) ; Wang, Ming-Wei(mwwang@simm.ac.cn) |
| 英文摘要 | Class IA phosphoinositide 3-kinase alpha (PI3K alpha) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3K alpha, the dimer of p110 alpha and p85 alpha, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3K alpha resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo-or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3K alpha. |
| WOS关键词 | INHIBITOR ; DISCOVERY ; 3-KINASE ; BINDING ; IDENTIFICATION ; ISOFORM ; POTENT ; MUTATIONS ; SYSTEM ; MUTANT |
| 资助项目 | National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; STI2030-Major Project[2021ZD0203400] ; National Key Basic Research Program of China[2018YFA0507000] ; Hainan Provincial Major Science and Technology Project[ZDKJ2021028] ; Novo Nordisk-ChineseAcademy of Sciences Research Fund grant[NNCAS-2017-1-CC] ; National Cancer Institute[R35 CA197582] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATL ACAD SCIENCES |
| WOS记录号 | WOS:001083521500011 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/307533]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Yang, Dehua; Vogt, Peter K.; Wang, Ming-Wei |
| 作者单位 | 1.Philochem AG, R&D Dept, CH-8112 Otelfingen, Switzerland 2.Hainan Med Coll, Sch Pharm, Haikou 570228, Hainan, Peoples R China 3.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan 4.Res Ctr Deepsea Bioresources, Sanya 572025, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 6.Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA 7.Swiss Fed Inst Technol, Dept Chem & Appl Biosci, CH-8093 Zurich, Switzerland 8.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Qingtong,Liu, Xiao,Neri, Dario,et al. Structural insights into the interaction of three Y- shaped ligands with PI3Kα[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2023,120(34):9. |
| APA | Zhou, Qingtong.,Liu, Xiao.,Neri, Dario.,Li, Wenxin.,Favalli, Nicholas.,...&Wang, Ming-Wei.(2023).Structural insights into the interaction of three Y- shaped ligands with PI3Kα.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,120(34),9. |
| MLA | Zhou, Qingtong,et al."Structural insights into the interaction of three Y- shaped ligands with PI3Kα".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120.34(2023):9. |
入库方式： OAI收割
来源：上海药物研究所
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