Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design.

IF 2.6 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Acta Crystallographica. Section D, Structural Biology Pub Date : 2023-10-01 Epub Date: 2023-09-15 DOI:10.1107/S2059798323006137

Rebecca Ebenhoch, Margit Bauer, Helmut Romig, Dirk Gottschling, Jörg Thomas Kley, Niklas Heine, Alexander Weber, Ingo Uphues, Herbert Nar, Alexander Pautsch

{"title":"Crystal structures of human and mouse ketohexokinase provide a structural basis for species- and isoform-selective inhibitor design.","authors":"Rebecca Ebenhoch, Margit Bauer, Helmut Romig, Dirk Gottschling, Jörg Thomas Kley, Niklas Heine, Alexander Weber, Ingo Uphues, Herbert Nar, Alexander Pautsch","doi":"10.1107/S2059798323006137","DOIUrl":null,"url":null,"abstract":"<p><p>A molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of D-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and intestinal isoform KHK-C and the peripheral isoform KHK-A. Here, the structure of apo murine KHK (mKHK), which differs from structures of human KHK in overall conformation, is reported. An isoform-selective ligand, which offers a 50-fold higher potency on mKHK and human KHK-A compared with KHK-C, is further characterized. In mKHK, large-scale conformational changes are observed upon ligand binding. The structures suggest a combined strategy for the design of species- and isoform-selective KHK inhibitors.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"871-880"},"PeriodicalIF":2.6000,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Crystallographica. Section D, Structural Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1107/S2059798323006137","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/9/15 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}

引用次数: 0

Abstract

A molecular understanding of the proteins involved in fructose metabolism is essential for controlling the current spread of fructose-related obesity, diabetes and related adverse metabolic states in Western populations. Fructose catabolism starts with the phosphorylation of D-fructose to fructose 1-phosphate by ketohexokinase (KHK). KHK exists in two alternatively spliced isoforms: the hepatic and intestinal isoform KHK-C and the peripheral isoform KHK-A. Here, the structure of apo murine KHK (mKHK), which differs from structures of human KHK in overall conformation, is reported. An isoform-selective ligand, which offers a 50-fold higher potency on mKHK and human KHK-A compared with KHK-C, is further characterized. In mKHK, large-scale conformational changes are observed upon ligand binding. The structures suggest a combined strategy for the design of species- and isoform-selective KHK inhibitors.

Abstract Image

查看原文本刊更多论文

人和小鼠酮己糖激酶的晶体结构为物种和异构体选择性抑制剂的设计提供了结构基础。

对果糖代谢相关蛋白质的分子理解对于控制目前西方人群中果糖相关肥胖、糖尿病和相关不良代谢状态的传播至关重要。果糖分解代谢始于酮己糖激酶（KHK）将D-果糖磷酸化为果糖1-磷酸。KHK存在于两种交替剪接的亚型中：肝和肠亚型KHK-C和外周亚型KHK-A。本文报道了apo鼠KHK（mKHK）的结构，它在整体构象上与人KHK的结构不同。进一步表征了一种异构体选择性配体，该配体对mKHK和人KHK-a的效力是KHK-C的50倍。在mKHK中，在配体结合时观察到大规模构象变化。这些结构为物种和异构体选择性KHK抑制剂的设计提供了一种组合策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Acta Crystallographica. Section D, Structural Biology BIOCHEMICAL RESEARCH METHODSBIOCHEMISTRY &-BIOCHEMISTRY & MOLECULAR BIOLOGY

CiteScore

4.50

自引率

13.60%

发文量

216

期刊介绍： Acta Crystallographica Section D welcomes the submission of articles covering any aspect of structural biology, with a particular emphasis on the structures of biological macromolecules or the methods used to determine them. Reports on new structures of biological importance may address the smallest macromolecules to the largest complex molecular machines. These structures may have been determined using any structural biology technique including crystallography, NMR, cryoEM and/or other techniques. The key criterion is that such articles must present significant new insights into biological, chemical or medical sciences. The inclusion of complementary data that support the conclusions drawn from the structural studies (such as binding studies, mass spectrometry, enzyme assays, or analysis of mutants or other modified forms of biological macromolecule) is encouraged. Methods articles may include new approaches to any aspect of biological structure determination or structure analysis but will only be accepted where they focus on new methods that are demonstrated to be of general applicability and importance to structural biology. Articles describing particularly difficult problems in structural biology are also welcomed, if the analysis would provide useful insights to others facing similar problems.