Structural and thermodynamic insights into the recognition of native proteins by anti-peptide antibodies.
Structural and thermodynamic insights into the recognition of native proteins by anti-peptide antibodies.
复制标题
抗肽抗体对天然蛋白识别的结构和热力学见解。
DOI：
10.1016/j.jmb.2013.02.031
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发表时间：
2013-06-12
影响因子：
5.6
通讯作者：
Amzel, L. Mario
中科院分区：
文献类型：
--
作者：
Armstrong, Anthony A.;Hildreth, James E. K.;Amzel, L. Mario
针对蛋白质衍生肽引发的抗体与其同源蛋白质实现交叉反应性的机制仍然未知。为了解决这个问题，我们对针对葡萄球菌核酸酶（SNase）衍生肽（SNpep）的单克隆抗体（260.33.12）与引发肽和同源蛋白的结合进行了完整的热力学表征。虽然两种配体的结合亲和力相似（蛋白质和肽的Kd分别为0.42 μM和0.30 μM），但蛋白质和肽的结合具有高度不同的热力学特征：肽结合的特征是大的熵贡献（ΔH = −7.7 kcal/mol），而蛋白质结合的主要特征是大的熵贡献（-TΔS = −7.2 kcal/mol）。的SNpep：Fab复合物的结构，通过X-射线衍射测定，揭示了结合构象的肽不同于相应的环区的构象中的晶体结构的游离SNase。通过分子动力学模拟估计的天然SNase和其中在Fab结合肽的构象中构建Ω环的模型之间的能量差表明，采用这种构象的能量成本与蛋白质维斯维斯肽结合的能量成本是相容的。这些结果与抗肽抗体识别同源蛋白质的机制是相容的：在结合非天然构象时，通过用降低的熵损失抵消双链罚分来维持高亲和力。这些发现提供了潜在的有用的指导方针，用于识别线性抗原决定簇内的蛋白质序列，非常适合于合成肽疫苗的发展。
The mechanism by which antibodies elicited against protein-derived peptides achieve cross-reactivity with their cognate proteins remains unknown. To address this question we have carried out the complete thermodynamic characterization of the association of a monoclonal antibody (260.33.12) raised against a peptide (SNpep) derived from staphylococcal nuclease (SNase) with both eliciting peptide and cognate protein. Although both ligands bind with similar affinity (Kd = 0.42 µM and 0.30 µM for protein and peptide, respectively), protein and peptide binding have highly different thermodynamic signatures: peptide binding is characterized by a large enthalpic contribution (ΔH = −7.7 kcal/mol) whereas protein binding is dominated by a large entropic contribution (-TΔS = −7.2 kcal/mol). The structure of the SNpep:Fab complex, determined by x-ray diffraction, reveals that the bound conformation of the peptide differs from the conformation of the corresponding loop region in crystal structures of free SNase. The energy difference, estimated by molecular dynamics simulations between native SNase and a model in which the Ω-loop is built in the conformation of the Fab-bound peptide, shows that the energetic cost of adopting this conformation is compatible with the enthalpic cost of binding the protein vis-à-vis the peptide. These results are compatible with a mechanism by which the anti-peptide antibody recognizes the cognate protein: high affinity is maintained upon binding a nonnative conformation by offsetting enthalpic penalties with reduced entropic losses. These findings provide potentially useful guidelines for the identification of linear epitopes within protein sequences that are well suited for the development of synthetic peptide vaccines.
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DOI：
10.1073/pnas.80.16.4949
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
NIMAN, HL;HOUGHTEN, RA;LERNER, RA
通讯作者：
LERNER, RA
影响因子：
5.7
作者：
Sharon, M;Kessler, N;Anglister, J
通讯作者：
Anglister, J
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
56.9
作者：
RINI, JM;SCHULZEGAHMEN, U;WILSON, IA
通讯作者：
WILSON, IA