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首页> 外文期刊>Clinical immunology: The official journal of the Clinical Immunology Society >Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency.
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Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency.

机译：Jak3激酶域的分子模型和严重联合免疫缺陷的结构基础。

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Hereditary severe combined immunodeficiency (SCID) includes a heterogeneous group of diseases that profoundly affect both cellular and humoral immune responses and require treatment by bone marrow transplantation. Characterization of the cellular and molecular bases of SCID is essential to provide accurate genetic counseling and prenatal diagnosis, and it may offer the grounds for alternative forms of treatment. The Jak3 gene is mutated in most cases of autosomal recessive T(-)B(+) SCID in humans. Jak3 belongs to the family of intracellular Janus tyrosine kinases. It is physically and functionally coupled to the common gamma chain, gammac, shared by several cytokine receptors. We have established the JAK3base registry for disease and mutation information. In order to study the structural consequences of the Jak3 mutations, the structure of the human Jak3 kinase and pseudokinase domains was modeled. Residues involved in ATP and Mg(2+) binding were highly conserved in the kinase domain whereas the substrate binding region is somewhat different compared to other kinases. We have identified the first naturally occurring mutations disrupting the function of the human Jak3 kinase domain. The structural basis of all of the known Jak3 mutations reported so far is discussed based on the modeled structure. The model of the Jak3 protein also permits us to study Jak3 phosphorylation at the structural level and may thus serve in the design of novel immune suppressive drugs. Copyright 2000 Academic Press.
机译：遗传性严重联合免疫缺陷症（SCID）包括一组异质性疾病，它们会深刻影响细胞和体液免疫反应，并需要通过骨髓移植进行治疗。 SCID的细胞和分子碱基的表征对于提供准确的遗传咨询和产前诊断至关重要，并且可以为其他治疗形式提供依据。在大多数人的常染色体隐性T（-）B（+）SCID病例中，Jak3基因发生突变。 Jak3属于细胞内Janus酪氨酸激酶家族。它在物理上和功能上与几种细胞因子受体共享的共同γ链gammac偶联。我们已经建立了JAK3base注册表，用于疾病和突变信息。为了研究Jak3突变的结构后果，对人Jak3激酶和假激酶结构域的结构进行了建模。参与ATP和Mg（2+）结合的残基在激酶域中高度保守，而底物结合区与其他激酶相比则有所不同。我们已经确定了第一个自然发生的突变，破坏了人类Jak3激酶结构域的功能。基于建模的结构，讨论了迄今为止报道的所有已知Jak3突变的结构基础。 Jak3蛋白的模型还使我们能够在结构水平上研究Jak3磷酸化，因此可能有助于新型免疫抑制药物的设计。版权所有2000学术出版社。

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