Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity
Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity
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DOI：
10.1172/jci13890
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发表时间：
2001-10-01
影响因子：
15.9
通讯作者：
Fremont, DH
中科院分区：
文献类型：
--
作者：
Lam, J;Nelson, CA;Fremont, DH
RANK（NF-κ B的受体激活剂）及其配体RANKL（最初称为TRANCE，也称为ODF和OPGL）是一种TNF超家族受体-配体对，控制破骨细胞、淋巴组织和乳腺上皮的发育和功能。虽然TNF家族细胞因子共享共同的结构支架，但个体受体-配体对与高特异性相关。鉴于TNF超家族成员之间氨基酸保守性水平较低，如果不了解其三维结构，就无法完全理解这些分子实现特异性的方法。为了确定介导RANK激活的RANKL元件，我们结晶了鼠RANKL的胞外域，并将其结构解析至2.6埃的分辨率。RANKL自身结合为具有四个独特表面环的同源三聚体，这将其与其他TNF家族细胞因子区分开来。这些环中选定残基的突变显著调节RANK活化，如体外破骨细胞生成所证明的，从而确定其在介导RANKL生物活性中的必要性。RANKL-RANK特异性的此类结构决定因素可能与化合物的药理学设计相关，以改善骨质减少性骨疾病。
RANK, the receptor activator of NF-kappaB, and its ligand RANKL (initially termed TRANCE, also termed ODF and OPGL), are a TNF superfamily receptor-ligand pair that govern the development and function of osteoclasts, lymphoid tissue, and mammary epithelium. While TNF family cytokines share a common structural scaffold, individual receptor-ligand pairs associate with high specificity. Given the low level of amino acid conservation among members of the TNF superfamily, the means by which these molecules achieve specificity cannot be completely understood without knowledge of their three-dimensional structures. To determine the elements of RANKL that mediate RANK activation, we have crystallized the ectodomain of murine RANKL and solved its structure to a resolution of 2.6 Angstrom. RANKL self-associates as a homotrimer with four unique surface loops that distinguish it from other TNF family cytokines. Mutagenesis of selected residues in these loops significantly modulates RANK activation, as evidenced by in vitro osteoclastogenesis, thereby establishing their necessity in mediating the biological activities of RANKL Such structural determinants of RANKL-RANK specificity may be of relevance in the pharmacologic design of compounds to ameliorate osteopenic disorders of bone.