Structural basis for substrate binding, catalysis and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2025-02-03 DOI:10.1016/j.str.2025.01.008

Merve Demir, Laura Koepping, Ya Li, Lynn Fujimoto, Andrey Bobkov, Jianhua Zhao, Taro Hitosugi, Eduard Sergienko

{"title":"Structural basis for substrate binding, catalysis and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor","authors":"Merve Demir, Laura Koepping, Ya Li, Lynn Fujimoto, Andrey Bobkov, Jianhua Zhao, Taro Hitosugi, Eduard Sergienko","doi":"10.1016/j.str.2025.01.008","DOIUrl":null,"url":null,"abstract":"Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The inhibition of breast cancer growth by cyclocreatine targeting CKs indicates dependence of cancer cells on the “energy shuttle” for cell growth and survival. Hence, understanding key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present mutational and structural investigations on understudied ubiquitous MtCK that showed closure of the loop comprising His61 is specific to and relies on creatine binding and mechanism of phosphoryl transfer depends on electrostatics of active site. We demonstrate that previously identified pan-CK covalent inhibitor CKi inhibit breast cancer cell proliferation; however, our biochemical and structural data indicated that inhibition by CKi is highly dependent on covalent link formation and conformational changes upon creatine binding are not observed.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"63 1","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Structure","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.str.2025.01.008","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The inhibition of breast cancer growth by cyclocreatine targeting CKs indicates dependence of cancer cells on the “energy shuttle” for cell growth and survival. Hence, understanding key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present mutational and structural investigations on understudied ubiquitous MtCK that showed closure of the loop comprising His61 is specific to and relies on creatine binding and mechanism of phosphoryl transfer depends on electrostatics of active site. We demonstrate that previously identified pan-CK covalent inhibitor CKi inhibit breast cancer cell proliferation; however, our biochemical and structural data indicated that inhibition by CKi is highly dependent on covalent link formation and conformational changes upon creatine binding are not observed.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.