大肠杆菌TrmB和抗ErbB2抗体chA21的结构生物学研究
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摘要
tRNA的成熟是一个包含了许多种转录后修饰的复杂过程。其中,可变环46位鸟嘌呤第7位N原子上的甲基化(m7G46)修饰是少有的几个能在碱基上引入正电荷的修饰之一。m7G46修饰广泛地存在于几乎所有细菌、真核生物和部分古细菌的第一类tRNA中。当缺乏m7G46与缺乏其它非致死tRNA修饰同时出现时,酵母细胞内的tRNA会被快速降解。
在这次工作中,我们解析了大肠杆菌tRNA(m7G46)甲基转移酶(EcTrmB)的高分辨率晶体结构。与其它先前报导的形成同源或异源二聚体的TrmB相似,EcTrmB也折叠成同一种修饰过的Rossmann折叠模式。但是,在对功能至关重要的一段TrmB特有的插入序列处,EcTrmB的结构与其同源蛋白质存在明显差异。在EcTrmB中,这段插入序列的COOH—端与S腺苷甲硫氨酸的结合口袋分离开若干埃,破坏了G46碱基的结合口袋。这暗示了,EcTrmB的这段插入序列可能需要经历一个结构重排才能结合和催化G46碱基。在先前报导的同源二聚化的TrmB中,二体中的另外一个亚基可以阻止这段插入序列与S腺苷甲硫氨酸的结合口袋的分离。在对应于其它同源二聚体TrmB的二聚化结合面处,EcTrmB的残基202—206和223—227形成了两个突出的loop。这些突出的loop可以产生空间排斥阻止EcTrmB形成类似的同源二聚体,这可能是EcTrmB以单体形式存在的重要原因。
ErbB2(Her2/neu/p185)是表皮生长因子(EGFR)家族的重要成员之一。如今,ErbB2已经变成了肿瘤治疗的重要靶标。中国科学技术大学刘兢教授等开发了一种抗ErbB2的嵌合抗体chA21。体内、体外实验均表明,chA21能够特异性地抑制ErbB2过表达的肿瘤细胞的生长。我们使用坐滴气相扩散法结晶了chA21的单链抗体(scFv)部分与ErbB2胞外区NH_2—端的前192个残基(命名为EPI)的复合物。复合物络构显示scFv的互补决定区的六个loop构成了一个大的口袋结合EPI上位于ErbB2二聚化结合面背面的三段不连续的loop。整个抗原—抗体结合面含有17对氢键和172个范德华相互作用。chA21被发现能够强烈地下调细胞表面ErbB2的水平,而且这种下调活性需要chA21的二价性。我们提出了一个模型:chA21可以通过它的两个scFv片段同时结合两个属于不同二聚体的ErbB2受体,并将这些二聚体交联成一个大复合物。这种大复合物能构被细胞自身发现,并内吞和降解,导致细胞ErbB2水平的降低。
古细菌的转录系统采用真核生物类型的RNA聚合酶和细菌类型的转录条件因子。NusG是少数几个在细菌、古细菌和真核生物等细胞生命的三个域中都发挥重要作用的转录因子。古细菌NusG的结构域组成与细菌NusG相似,包含一个NGN和一个KOW结构域,远较其在真核生物中的直系同源蛋白质Spt5简单。但是,最近我们实验室的数据显示,古细菌NusG可以与rpoE”蛋白质形成复合物。这一性质与真核生物Spt5-Spt4复合物相似。
在本论文中,我们报导了吉细菌Methanocaldococcus jannaschii NusG的NGN结构域的晶体结构。MjNGN采用a-β-a的三明治折叠模式,不具有细菌NGN的附加结构域。在晶体和溶液中,MjNGN均能够形成同源二聚体。实验数据表明,MjNGN单独即可以与rpoE”结合。我们用刚体对接程序搭建了MjNGN—rpoE”的复合物结构模型,并用突变分析验证了模型的正确性。最近,我们初步解析了MjNusG-rpoE”复合物的晶体结构,进一步的结构和生化功能分析还在进行中。
The maturation of tRNAs is a complex process involving numerous post-transcriptional modifications.N7-methylguanosine modification at position 46 (m7G46) in the variable loop is one of the few modifications that introduce a positive charge to the base,and is conserved in almost all of classⅠtRNAs in bacteria, eukaryotes and some archaea.When lacking m7G46 in combination with other non-essential modifications,the yeast cellular tRNAs are sent to the rapid tRNA degradation(RTD) pathway.
Here,we determined the crystal structure of E.coli tRNA(m7G46) methyltransferase(EcTrmB) at high resolution.Similar to its homo- or heterodimeric homologues,EcTrmB also adopts a modified Rossmann fold.But,the function-essential insertion of EcTrmB has a conformation different to all of its homologues.In EcTrmB,the C-terminal part of this insertion separates from the S-adenosyl-L-methionine(SAM) binding site for several angstroms,which destroys the binding pocket for base G46.It seems that a structural rearrangement of the insertion of EcTrmB is required to form the G46 pocket during catalysis.In contrast, in homodimeric TrmBs,the steric hindrance from the other subunit prevents the C-terminal part of the insertion separating from the SAM-binding site.Residues 202-206 and 223-227 of EcTrmB form two protruding loops at the dimeric interface of other homodimeric TrmBs.These protruding loops would cause many conflicts if EcTrmB formed a homodimer,which provides the structural insight to why monomeric TrmBs cannot form dimers.
ErbB2(Her2/neu/p185) is a key member of epidermal growth factor receptor (EGFR) family,which has become an attractive target for therapeutic intervention. Prof.Jing Liu and her colleagues at USTC previously developed an anti-ErbB2 chimeric antibody chA21 that could specifically inhibit the growth of ErbB2-overexpressing cancer cells in vitro and in vivo.
Herein,the antibody-antigen complex consists of the single-chain variable fragment(scFv) of chA21 and an N-terminal fragment(residues 1-192,named EPⅠ) of ErbB2 extracellular domain was crystallized.The complex structure shows that the complementarity determining regions(CDR) of chA21 form a vast pocket to bind to three loops at the backside of ErbB2 ECD dimerization interface.The antibody-antigen interface contains 17 specific hydrogen bonds and 172 van der Waals contacts. chA21 was also found to have a strong bivalency-dependent effect of on down-regulating ErbB2.We proposed a model that chA21 could capture two ErbB2 molecules belonging to separate homo- or hetero- dimers and cross-link these dimers to form a large complex.The large complex contains the ErbB2 could be internalized and degradated efficiently.
Transcription in archaea employs a eukaryotic-type transcription apparatus but uses bacterial-type transcription factors.NusG is one of the few archaeal transcription factors whose orthologs are essential in both bacteria and eukaryotes.Archaeal NusG is composed of only an NusG N-terminal(NGN) domain and a KOW domain,which is similar to bacterial NusG but not to the eukaryotic ortholog,Spt5.However, archaeal NusG was confirmed recently to form a complex with rpoE" that was similar to the Spt5-Spt4 complex.
In this work,we report the crystal structure of NGN domain from the archaea Methanocaldococcus jannaschii(MjNGN).MjNGN folds to an a-β-a sandwich without the appendant domain of bacterial NGNs,and forms a unique homodimer in crystal and solution.MjNGN alone was found to be sufficient for rpoE" binding and an MjNGN-rpoE" model has been constructed by rigid docking and validated by mutagenesis analysis.Furthermore,we have determined the crystal structure of MjNusG-rpoE" complex very recently.Futher structural and biochemical analysis of this complex is still under way.
在这次工作中,我们解析了大肠杆菌tRNA(m7G46)甲基转移酶(EcTrmB)的高分辨率晶体结构。与其它先前报导的形成同源或异源二聚体的TrmB相似,EcTrmB也折叠成同一种修饰过的Rossmann折叠模式。但是,在对功能至关重要的一段TrmB特有的插入序列处,EcTrmB的结构与其同源蛋白质存在明显差异。在EcTrmB中,这段插入序列的COOH—端与S腺苷甲硫氨酸的结合口袋分离开若干埃,破坏了G46碱基的结合口袋。这暗示了,EcTrmB的这段插入序列可能需要经历一个结构重排才能结合和催化G46碱基。在先前报导的同源二聚化的TrmB中,二体中的另外一个亚基可以阻止这段插入序列与S腺苷甲硫氨酸的结合口袋的分离。在对应于其它同源二聚体TrmB的二聚化结合面处,EcTrmB的残基202—206和223—227形成了两个突出的loop。这些突出的loop可以产生空间排斥阻止EcTrmB形成类似的同源二聚体,这可能是EcTrmB以单体形式存在的重要原因。
ErbB2(Her2/neu/p185)是表皮生长因子(EGFR)家族的重要成员之一。如今,ErbB2已经变成了肿瘤治疗的重要靶标。中国科学技术大学刘兢教授等开发了一种抗ErbB2的嵌合抗体chA21。体内、体外实验均表明,chA21能够特异性地抑制ErbB2过表达的肿瘤细胞的生长。我们使用坐滴气相扩散法结晶了chA21的单链抗体(scFv)部分与ErbB2胞外区NH_2—端的前192个残基(命名为EPI)的复合物。复合物络构显示scFv的互补决定区的六个loop构成了一个大的口袋结合EPI上位于ErbB2二聚化结合面背面的三段不连续的loop。整个抗原—抗体结合面含有17对氢键和172个范德华相互作用。chA21被发现能够强烈地下调细胞表面ErbB2的水平,而且这种下调活性需要chA21的二价性。我们提出了一个模型:chA21可以通过它的两个scFv片段同时结合两个属于不同二聚体的ErbB2受体,并将这些二聚体交联成一个大复合物。这种大复合物能构被细胞自身发现,并内吞和降解,导致细胞ErbB2水平的降低。
古细菌的转录系统采用真核生物类型的RNA聚合酶和细菌类型的转录条件因子。NusG是少数几个在细菌、古细菌和真核生物等细胞生命的三个域中都发挥重要作用的转录因子。古细菌NusG的结构域组成与细菌NusG相似,包含一个NGN和一个KOW结构域,远较其在真核生物中的直系同源蛋白质Spt5简单。但是,最近我们实验室的数据显示,古细菌NusG可以与rpoE”蛋白质形成复合物。这一性质与真核生物Spt5-Spt4复合物相似。
在本论文中,我们报导了吉细菌Methanocaldococcus jannaschii NusG的NGN结构域的晶体结构。MjNGN采用a-β-a的三明治折叠模式,不具有细菌NGN的附加结构域。在晶体和溶液中,MjNGN均能够形成同源二聚体。实验数据表明,MjNGN单独即可以与rpoE”结合。我们用刚体对接程序搭建了MjNGN—rpoE”的复合物结构模型,并用突变分析验证了模型的正确性。最近,我们初步解析了MjNusG-rpoE”复合物的晶体结构,进一步的结构和生化功能分析还在进行中。
The maturation of tRNAs is a complex process involving numerous post-transcriptional modifications.N7-methylguanosine modification at position 46 (m7G46) in the variable loop is one of the few modifications that introduce a positive charge to the base,and is conserved in almost all of classⅠtRNAs in bacteria, eukaryotes and some archaea.When lacking m7G46 in combination with other non-essential modifications,the yeast cellular tRNAs are sent to the rapid tRNA degradation(RTD) pathway.
Here,we determined the crystal structure of E.coli tRNA(m7G46) methyltransferase(EcTrmB) at high resolution.Similar to its homo- or heterodimeric homologues,EcTrmB also adopts a modified Rossmann fold.But,the function-essential insertion of EcTrmB has a conformation different to all of its homologues.In EcTrmB,the C-terminal part of this insertion separates from the S-adenosyl-L-methionine(SAM) binding site for several angstroms,which destroys the binding pocket for base G46.It seems that a structural rearrangement of the insertion of EcTrmB is required to form the G46 pocket during catalysis.In contrast, in homodimeric TrmBs,the steric hindrance from the other subunit prevents the C-terminal part of the insertion separating from the SAM-binding site.Residues 202-206 and 223-227 of EcTrmB form two protruding loops at the dimeric interface of other homodimeric TrmBs.These protruding loops would cause many conflicts if EcTrmB formed a homodimer,which provides the structural insight to why monomeric TrmBs cannot form dimers.
ErbB2(Her2/neu/p185) is a key member of epidermal growth factor receptor (EGFR) family,which has become an attractive target for therapeutic intervention. Prof.Jing Liu and her colleagues at USTC previously developed an anti-ErbB2 chimeric antibody chA21 that could specifically inhibit the growth of ErbB2-overexpressing cancer cells in vitro and in vivo.
Herein,the antibody-antigen complex consists of the single-chain variable fragment(scFv) of chA21 and an N-terminal fragment(residues 1-192,named EPⅠ) of ErbB2 extracellular domain was crystallized.The complex structure shows that the complementarity determining regions(CDR) of chA21 form a vast pocket to bind to three loops at the backside of ErbB2 ECD dimerization interface.The antibody-antigen interface contains 17 specific hydrogen bonds and 172 van der Waals contacts. chA21 was also found to have a strong bivalency-dependent effect of on down-regulating ErbB2.We proposed a model that chA21 could capture two ErbB2 molecules belonging to separate homo- or hetero- dimers and cross-link these dimers to form a large complex.The large complex contains the ErbB2 could be internalized and degradated efficiently.
Transcription in archaea employs a eukaryotic-type transcription apparatus but uses bacterial-type transcription factors.NusG is one of the few archaeal transcription factors whose orthologs are essential in both bacteria and eukaryotes.Archaeal NusG is composed of only an NusG N-terminal(NGN) domain and a KOW domain,which is similar to bacterial NusG but not to the eukaryotic ortholog,Spt5.However, archaeal NusG was confirmed recently to form a complex with rpoE" that was similar to the Spt5-Spt4 complex.
In this work,we report the crystal structure of NGN domain from the archaea Methanocaldococcus jannaschii(MjNGN).MjNGN folds to an a-β-a sandwich without the appendant domain of bacterial NGNs,and forms a unique homodimer in crystal and solution.MjNGN alone was found to be sufficient for rpoE" binding and an MjNGN-rpoE" model has been constructed by rigid docking and validated by mutagenesis analysis.Furthermore,we have determined the crystal structure of MjNusG-rpoE" complex very recently.Futher structural and biochemical analysis of this complex is still under way.
引文
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