A small step towards an important goal: fragment screen of the c-di-AMP-synthesizing enzyme CdaA.

IF 2.6 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Acta Crystallographica. Section D, Structural Biology Pub Date : 2024-05-01 Epub Date: 2024-04-29 DOI:10.1107/S205979832400336X

Piotr Neumann, Jana L Heidemann, Jan Wollenhaupt, Achim Dickmanns, Michael Agthe, Manfred S Weiss, Ralf Ficner

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Abstract

CdaA is the most widespread diadenylate cyclase in many bacterial species, including several multidrug-resistant human pathogens. The enzymatic product of CdaA, cyclic di-AMP, is a secondary messenger that is essential for the viability of many bacteria. Its absence in humans makes CdaA a very promising and attractive target for the development of new antibiotics. Here, the structural results are presented of a crystallographic fragment screen against CdaA from Listeria monocytogenes, a saprophytic Gram-positive bacterium and an opportunistic food-borne pathogen that can cause listeriosis in humans and animals. Two of the eight fragment molecules reported here were localized in the highly conserved ATP-binding site. These fragments could serve as potential starting points for the development of antibiotics against several CdaA-dependent bacterial species.

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向重要目标迈出的一小步：c-di-AMP 合成酶 CdaA 的片段筛选。

CdaA 是许多细菌物种中最常见的二腺苷酸环化酶，其中包括几种具有多重耐药性的人类病原体。CdaA 的酶促产物环二-AMP 是一种次级信使，对许多细菌的生存至关重要。人类体内缺乏这种物质，因此 CdaA 成为开发新型抗生素的一个非常有前景和吸引力的目标。单核细胞增生李斯特菌是一种溶菌性革兰氏阳性细菌，也是一种机会性食源性致病菌，可导致人类和动物患李斯特菌病，本文介绍了针对单核细胞增生李斯特菌 CdaA 的晶体学片段筛选的结构结果。本文报告的八个片段分子中有两个位于高度保守的 ATP 结合位点。这些片段可作为开发抗生素的潜在起点，以对付多种依赖 CdaA 的细菌。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.