Crystal structure of FadR, a fatty acid-responsive transcription factor with a novel acyl coenzyme A-binding fold
Crystal structure of FadR, a fatty acid-responsive transcription factor with a novel acyl coenzyme A-binding fold
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DOI：
10.1093/emboj/19.19.5167
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发表时间：
2000-10-02
期刊：
影响因子：
11.4
通讯作者：
Wierenga, RK
中科院分区：
文献类型：
--
作者：
van Aalten, DMF;DiRusso, CC;Wierenga, RK
FadR是二聚酰基辅酶A（酰基CoA）结合蛋白和转录因子，其调节大肠杆菌中编码脂肪酸生物合成和降解酶的基因的表达。在此，描述了全长FadR的2.0埃晶体结构，其使用多波长异常色散测定，该结构揭示了二聚体和双结构域折叠，与已知结构的比较和突变数据的分析描绘了与DNA相互作用的位点，C-末端结构域有一个新的折叠，由一个交叉拓扑结构的七螺旋束组成，仔细分析的结构，连同突变和生物物理数据，揭示了一个假定的疏水酰基辅酶A结合位点，埋在核心的七螺旋束。这种结构有助于在分子水平上理解FadR的功能，为转录因子的大GntR家族提供了第一个结构支架，这些转录因子是控制细菌病原体代谢的关键，因此可能是新型化疗药物的可能靶点。
FadR is a dimeric acyl coenzyme A (acyl CoA)-binding protein and transcription factor that regulates the expression of genes encoding fatty acid biosynthetic and degrading enzymes in Escherichia coli, Here, the 2.0 Angstrom crystal structure of full-length FadR is described, determined using multi-wavelength anomalous dispersion, The structure reveals a dimer and a two-domain fold, with DNA-binding and acyl-CoA-binding sites located in an N-terminal and C-terminal domain, respectively, The N-terminal domain contains a winged helix-turn-helix prokaryotic DNA-binding fold, Comparison with known structures and analysis of mutagenesis data delineated the site of interaction with DNA, The C-terminal domain has a novel fold, consisting of a seven-helical bundle with a crossover topology, Careful analysis of the structure, together with mutational and biophysical data, revealed a putative hydrophobic acyl-CoA-binding site, buried in the core of the seven-helical bundle. This structure aids in understanding FadR function at a molecular level, provides the first structural scaffold for the large GntR family of transcription factors, which are keys in the control of metabolism in bacterial pathogens, and could thus be a possible target for novel chemotherapeutic agents.