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首页> 外文期刊>Journal of Molecular Biology >The crystal structure of human pyrin b30.2 domain: implications for mutations associated with familial Mediterranean fever.
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The crystal structure of human pyrin b30.2 domain: implications for mutations associated with familial Mediterranean fever.

机译：人类吡啶b30.2结构域的晶体结构：对家族性地中海热相关突变的影响。

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摘要

The inherited autoinflammatory syndrome familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever, which are independent of any bacterial or viral infections. This disease is associated with point mutations in the mefv gene product pyrin. Although the precise molecular functions of pyrin are unknown, it seems to be involved in the maturation and secretion of interleukin-1beta. Approximately two thirds of all FMF-associated mutations cluster in the C-terminal B30.2 domain of pyrin. To investigate the molecular consequences of FMF-associated mutations, we determined the crystal structure of the pyrin B30.2 domain at 1.35-A resolution. The comparison with other B30.2/ligand complex structures revealed a shallow cavity, which seems to be involved in binding the pyrin ligand. The bottom of this cavity is covered mainly with hydrophobic amino acids, suggesting that pyrin recognizes its ligand by hydrophobic contacts and surface complementarities. FMF-associated mutations cluster around two sites on the B30.2 surface. Approximately two thirds, including those mutations with the most severe disease outcomes, are observed in the vicinity of the predicted peptide binding site, suggesting that they will have a direct impact on ligand binding. A second mutational hot spot was observed on the opposite side of the B30.2 domain in the neighbourhood of its artificial N-terminus. Although most FMF-associated mutations are solvent exposed, several will modify the main-chain conformation of loops. The experimental crystal structure of the pyrin B30.2 domain serves as a basis for an accurate modelling of these mutations.
机译：遗传性自发性炎症家族性地中海热（FMF）的特征是反复发作的发烧，与任何细菌或病毒感染无关。该疾病与mefv基因产物pyrin的点突变有关。尽管吡啶的确切分子功能尚不清楚，但似乎与白细胞介素-1β的成熟和分泌有关。所有与FMF相关的突变中，大约有三分之二聚集在吡啶的C端B30.2结构域中。为了调查与FMF相关的突变的分子后果，我们确定了1.35A分辨率的吡啶B30.2结构域的晶体结构。与其他B30.2 /配体复杂结构的比较显示出一个浅腔，似乎与结合吡啶配体有关。该腔的底部主要被疏水性氨基酸覆盖，这表明吡喃通过疏水性接触和表面互补性识别其配体。与FMF相关的突变聚集在B30.2表面的两个位点附近。在预测的肽结合位点附近观察到大约三分之二的突变，包括那些具有最严重疾病结果的突变，表明它们将直接影响配体结合。在人工N端附近的B30.2域的相对侧观察到第二个突变热点。尽管大多数与FMF相关的突变都暴露在溶剂中，但有些突变会修饰环的主链构象。吡啶B30.2结构域的实验晶体结构为这些突变的精确建模提供了基础。

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