Mechanisms of BMP Receptor Kinase Dysregulation in Skeletal Dysplasias

骨骼发育不良中 BMP 受体激酶失调的机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): Project Summary An single mutation (617G>A; Arg206His) within the kinase domain of just one of four human bone morphogenetic protein (BMP) receptors (ACVR1, ALK2) has recently been linked to the most catastrophic disorder of secondary (heterotopic) bone formation known to mankind. As a result of this identical substitution with histidine, all children presenting with features of classic FOP (Fibrodysplasia Ossificans Progressiva) eventually become encased in, and their movement blocked by, a second heterotopic skeleton. Because the cytoplasmic domains of the superfamily (TGF-2, transforming growth factor-2) of receptors are highly homologous, previously determined crystal structures of the TGF-2 type I receptor (T2RI) kinase domain in complex with the inhibitory protein FKBP12 and an ATP-analog small molecule inhibitor have lead to reliable structure-based homology models for interpreting the structural basis of altered BMP receptor kinase function in FOP. In this context, Arg206 appears to form a highly conserved ion pair with Asp269, situated in the glycine-serine rich (GS) regulatory region adjacent to the inhibitory protein (FKBP12) binding interface. Because the sidechain imidazole of histidine protonates and deprotonates within the physiological pH range, His-Asp ion pairs play unique roles in health and disease, acting as pH-sensitive switches for binding and release of O2 and CO2 by hemoglobin, and in a pH-sensitive molecular defect in the p53 tumor suppressor linked to a rare genetic disorder afflicting children in Brazil. Thus substitution with histidine, and only histidine, is predicted to induce a pH-sensitive conformational change in the protein backbone that leads to ligand-independent activation of the receptor under the hypoxic conditions of inflammation, postulated as an underlying trigger of episodes of explosive bone growth or "flare-ups" resulting from injuries to soft tissues. We will: (1) test this hypothetical pH-dependent mechanism of loss of autoinhibition by in vitro interaction analyses with the BMP kinase and FKBP12 by Surface Plasmon Resonance (SPR, BIAcore) assays, and (2) determine the crystal structures of the wildtype and Arg206His BMP kinases at physiological and hypoxic pH to identify precisely how the mutation perturbs the three- dimensional structure of the enzyme. These resulting structures will allow for optimization by rational design of a recently identified inhibitor (Dorsomorphin; a pyrrazolopyrimidine ATP-competitor) as a therapeutic drug targeted at the mutant kinase to block accumulation of extraskeletal bone in FOP, as well as the skeletal metastases of prostate cancer, the most common malignancy in men often resulting from stimulation of BMP receptor kinases.
描述(由申请人提供): 人类骨形态发生蛋白(BMP)受体(ACVR 1,ALK 2)的激酶结构域中的一个突变(617 G>A; Arg 206 His)最近被认为与人类已知的最严重的继发性(异位)骨形成疾病有关。由于组氨酸的这种相同取代,所有表现出典型FOP(进行性骨化性纤维发育不良)特征的儿童最终都会被第二个异位骨骼包裹,并且他们的运动会被第二个异位骨骼阻断。因为超家族的细胞质区域受体(TGF-2,转化生长因子-2)高度同源,先前确定的TGF-2 I型受体(T2 RI)激酶结构域与抑制性蛋白FKBP 12和ATP类似物小分子抑制剂复合的晶体结构导致了可靠的结构-基于同源性模型,用于解释FOP中BMP受体激酶功能改变的结构基础。在这种情况下,Arg 206似乎与Asp 269形成高度保守的离子对,位于与抑制性蛋白(FKBP 12)结合界面相邻的富含甘氨酸-丝氨酸(GS)的调控区。由于组氨酸的侧链咪唑在生理pH范围内质子化和去质子化,His-Asp离子对在健康和疾病中发挥独特的作用,作为血红蛋白结合和释放O2和CO2的pH敏感开关,以及与巴西儿童罕见遗传疾病相关的p53肿瘤抑制因子中的pH敏感分子缺陷。因此,预测用组氨酸取代,并且仅用组氨酸取代,诱导蛋白质骨架中的pH敏感性构象变化,其导致在炎症的缺氧条件下受体的配体非依赖性活化,假定为爆发性骨生长或由软组织损伤引起的“突发”事件的潜在触发因素。我们将:(1)通过表面等离子体共振(SPR,BIAcore)测定,通过与BMP激酶和FKBP 12的体外相互作用分析,测试这种假设的pH依赖性的自抑制丧失机制,和(2)确定野生型和Arg 206 His BMP激酶在生理和缺氧pH下的晶体结构,以精确鉴定突变如何扰乱酶的三维结构。这些得到的结构将允许通过合理设计最近鉴定的抑制剂(Dorsomorphin;吡唑并嘧啶ATP竞争剂)来优化,所述抑制剂作为靶向突变激酶的治疗药物以阻断FOP中骨骼外骨的积累以及前列腺癌的骨骼转移,前列腺癌是男性中最常见的恶性肿瘤,通常由BMP受体激酶的刺激引起。

项目成果

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Jay Clemens Groppe其他文献

Jay Clemens Groppe的其他文献

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{{ truncateString('Jay Clemens Groppe', 18)}}的其他基金

Mechanisms of BMP Receptor Kinase Dysregulation in Skeletal Dysplasias
骨骼发育不良中 BMP 受体激酶失调的机制
  • 批准号:
    7576671
  • 财政年份:
    2008
  • 资助金额:
    $ 7.25万
  • 项目类别:
Mechanisms of BMP Receptor Kinase Dysregulation in Skeletal Dysplasias
骨骼发育不良中 BMP 受体激酶失调的机制
  • 批准号:
    7999252
  • 财政年份:
    2008
  • 资助金额:
    $ 7.25万
  • 项目类别:
LIGAND-RECEPTOR INTERACTIONS IN THE TGF-BETA SUPERFAMILY
TGF-β 超家族中的配体-受体相互作用
  • 批准号:
    7598263
  • 财政年份:
    2007
  • 资助金额:
    $ 7.25万
  • 项目类别:

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