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首页> 外文期刊>Journal of Molecular Biology >Crystal structures of Streptococcus pneumoniaeN-acetylglucosamine-1-phosphate uridyltransferase, GlmU, in apo form at2.33 A resolution and in complex with UDP-N-acetylglucosamine and Mg2+ at1.96 A resolution
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Crystal structures of Streptococcus pneumoniaeN-acetylglucosamine-1-phosphate uridyltransferase, GlmU, in apo form at2.33 A resolution and in complex with UDP-N-acetylglucosamine and Mg2+ at1.96 A resolution

机译：肺炎链球菌N-乙酰氨基葡糖-1-磷酸尿嘧啶转移酶GlmU的晶体结构，载脂蛋白形式at2.33 A分辨率并与UDP-N-乙酰氨基葡萄糖和Mg2 +的复合物at1.96 A分辨率

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摘要

N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is an essential bacterial enzyme with both an acetyltransferase and a uridyltransferase activity which have been mapped to the C-terminal and N-terminal domains, respectively. GlmU performs the last two steps in the synthesis of UDP-N-acetylglucosamine (UDP-GlcNAc), which is an essential precursor in both the peptidoglycan and the lipopolysaccharide metabolic pathways. GlmU is therefore an attractive target for potential antibiotics. Knowledge of its three-dimensional structure would provide a basis for rational drug design. We have determined the crystal structures of Streptococcus pneumoniae GlmU (SpGlmU) in apo form at 2.33 Angstrom resolution, and in complex with UDP-N-acetyl glucosamine and the essential co-factor Mg2+ at 1.96 Angstrom resolution. The protein structure consists of an N-terminal domain with an alpha/beta -fold, containing the uridyltransferase active site, and a C-terminal domain with a long left-handed beta -sheet helix (L betaH) domain. An insertion loop containing the highly conserved sequence motif Asn-Tyr-Asp-Gly protrudes from the left-handed beta -sheet helix domain. Ln the crystal, S. pneumoniae GlmU forms exact trimers, mainly through contacts between left-handed beta -sheet helix domains. UDP-N-acetylglucosamine and Mg2+ are bound at the uridyltransferase active site, which is in a closed form. We propose a uridyltransferase mechanism in which the activation energy of the double negatively charged phosphorane transition state is lowered by charge compensation of Mg2+ and the side-chain of Lys22.
机译：N-乙酰氨基葡萄糖-1-磷酸尿嘧啶转移酶（GlmU）是一种必需的细菌酶，具有乙酰转移酶和尿嘧啶转移酶活性，分别定位于C端和N端域。 GlmU执行UDP-N-乙酰氨基葡萄糖（UDP-GlcNAc）的合成的最后两个步骤，UDP-N-乙酰氨基葡萄糖是肽聚糖和脂多糖代谢途径中必不可少的前体。因此，GlmU是潜在抗生素的诱人靶标。对其三维结构的了解将为合理的药物设计提供基础。我们已经确定了2.33埃分辨率的apo形式的肺炎链球菌GlmU（SpGlmU）的晶体结构，并在1.96埃分辨率下与UDP-N-乙酰基氨基葡萄糖和必需的辅因子Mg2 +形成了复合物。蛋白质结构由具有尿嘧啶转移酶活性位点的具有α/β-折叠的N-末端结构域和具有长的左手β-折叠螺旋（L betaH）结构域的C-末端结构域组成。包含高度保守的序列基序Asn-Tyr-Asp-Gly的插入环从左手β-sheet螺旋结构域突出。在晶体中，肺炎链球菌GlmU主要通过左手β-sheet螺旋结构域之间的接触形成精确的三聚体。 UDP-N-乙酰氨基葡萄糖和Mg2 +结合在呈封闭形式的uridyltransferase活性位点上。我们提出了一种uridyltransferase机制，其中通过Mg2 +和Lys22的侧链的电荷补偿降低了双负电荷磷烷过渡态的活化能。

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