Biophysical rescue of Coagulation Factor IXa conformational ensembles from hemophilia B disease mutations

从血友病 B 疾病突变中生物物理拯救凝血因子 IXa 构象整体

基本信息

项目摘要

 DESCRIPTION (provided by applicant): The broad goal of the proposed research is to gain a deeper understanding of the molecular mechanisms underlying hemophilia B. The blood coagulation cascade is a complex biochemical system that is regulated extensively in order to achieve hemostasis without inducing thrombosis. A key component in the activation and regulation of sustained coagulation is a protein complex known as the intrinsic Xase. This complex consists of the Factor IXa (fIXa) enzyme, along with its allosteric activator Factor VIIIa (fVIIIa) and several metal ions which also modulate its activity. Hemophilia B is caused by dysfunction of fIXa, the catalytic subunit of the intrinsic Xase. A specific subset of mutations tht cause hemophilia B do not affect the concentration of fIXa in the blood and do not significantly destabilize the protein. However, these mutations do impair the catalytic function of fIXa. We hypothesize that these mutations perturb conformational equilibria that are critical for allosteric communication, substrate binding, and enzymatic turnover. In order to test this hypothesis, we will first dissect allosteric communication pathways in fIXa using multi-temperature X-ray crystallography and computational approaches. These analyses will identify correlated conformational heterogeneity and energetic coupling between distal regions of the enzyme. Next, we will apply this same methodology to fIXa point mutants that are associated with hemophilia B. Combined with functional assays, this information will allow us to quantitatively understand how mutational perturbations to the conformational ensemble effect enzymatic activity. Finally, we will rationally engineer fIXa mutations whose effects suppress the disease phenotype in hemophilia B variants. This strategy of rescuing function by restoring the native fIXa conformational ensemble will inform future development of therapeutics by identifying allosteric networks that can be targeted with small molecules. Looking forward, the methodology of biophysical rescue that we will establish can be applied to other genetic diseases that result from single point mutations.
 描述(由申请人提供):拟议研究的广泛目标是更深入地了解血友病B的分子机制。凝血级联是一个复杂的生化系统,其被广泛调节以实现止血而不诱导血栓形成。激活和调节持续凝血的关键组分是称为内源性Xase的蛋白质复合物。该复合物由因子IXa(fIXa)酶、沿着其变构激活剂因子VIIIa(fVIIIa)和也调节其活性的几种金属离子组成。血友病B是由fIXa功能障碍引起的,fIXa是内源性Xase的催化亚基。引起血友病B的特定突变亚组不影响血液中fIXa的浓度,也不显著破坏蛋白质的稳定性。然而,这些突变确实损害了fIXa的催化功能。我们假设这些突变扰乱了对变构至关重要的构象平衡。 通讯、底物结合和酶周转。为了验证这一假设,我们将首先使用多温X射线晶体学和计算方法解剖fIXa中的变构通信途径。这些分析将确定相关的构象异质性和酶的远端区域之间的能量耦合。接下来,我们将把同样的方法应用于与血友病B相关的fIXa点突变体。结合功能测定,这些信息将使我们能够定量地了解突变扰动的构象合奏效果酶的活性。最后,我们将合理地设计fIXa突变,其作用抑制血友病B变体中的疾病表型。这种通过恢复天然fIXa构象整体来挽救功能的策略将通过鉴定可以用小分子靶向的变构网络来告知治疗剂的未来发展。展望未来,我们将建立的生物物理拯救方法可以应用于由单点突变引起的其他遗传疾病。

项目成果

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Michael C. Thompson其他文献

Comparison of Values Generated During Testing of the Knee Using the Cybex II Plus® and Biodex Model B-2000® Isokinetic Dynamometers1
使用 Cybex II Plus® 和 Biodex Model B-2000® 等速测力计测试膝关节时生成的值的比较1
Is Glutamate-Induced Reduction in Growth Hormone-Releasing Hormone a Neuroendocrine Model of Aging in the Rat?
谷氨酸诱导的生长激素释放激素减少是大鼠衰老的神经内分泌模型吗?
Generation of bright monomeric red fluorescent proteins emvia/em computational design of enhanced chromophore packing
通过增强生色团堆积的计算设计产生明亮的单体红色荧光蛋白
  • DOI:
    10.1039/d1sc05088e
  • 发表时间:
    2022-02-02
  • 期刊:
  • 影响因子:
    7.400
  • 作者:
    Sandrine Legault;Derek P. Fraser-Halberg;Ralph L. McAnelly;Matthew G. Eason;Michael C. Thompson;Roberto A. Chica
  • 通讯作者:
    Roberto A. Chica
Solvens‐induzierte reduktive Aktivierung von CO2 durch Bismut und Änderung des Reaktionsprodukts von Metalloformiat nach Oxalat
铋和草酸金属形成反应产品中的 CO2 溶剂还原活性
  • DOI:
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michael C. Thompson;J. Ramsay;J. Weber
  • 通讯作者:
    J. Weber
Pseudomonas fluorescens isocyanide hydratase at 274 K G150A mutant
荧光假单胞菌异氰化物水合酶 274 K G150A 突变体
  • DOI:
    10.2210/pdb6ni4/pdb
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    2.7
  • 作者:
    M. Dasgupta;D. Budday;S.H.P. de Oliveira;Peter Madzelan;Darya Marchany;J. Seravalli;Brandon Hayes;R. Sierra;S. Boutet;Hunter;R. Alonso;A. Batyuk;J. Wierman;A. Lyubimov;A. Brewster;N. Sauter;Gregory A. Applegate;V. K. Tiwari;David B. Berkowitz;Michael C. Thompson;Aina E. Cohen;James S. Fraser;Michael E. Wall;H. V. D. Bedem;Wilson
  • 通讯作者:
    Wilson

Michael C. Thompson的其他文献

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{{ truncateString('Michael C. Thompson', 18)}}的其他基金

Exploiting temperature-sensitive orthologs to understand protein allostery
利用温度敏感的直系同源物来了解蛋白质变构
  • 批准号:
    10716051
  • 财政年份:
    2023
  • 资助金额:
    $ 5.92万
  • 项目类别:
Biophysical rescue of Coagulation Factor IXa conformational ensembles from hemophilia B disease mutations
从血友病 B 疾病突变中生物物理拯救凝血因子 IXa 构象整体
  • 批准号:
    8981574
  • 财政年份:
    2015
  • 资助金额:
    $ 5.92万
  • 项目类别:
Biophysical rescue of Coagulation Factor IXa conformational ensembles from hemophilia B disease mutations
从血友病 B 疾病突变中生物物理拯救凝血因子 IXa 构象整体
  • 批准号:
    9391143
  • 财政年份:
    2015
  • 资助金额:
    $ 5.92万
  • 项目类别:
Biophysical rescue of Coagulation Factor IXa conformational ensembles from hemophilia B disease mutations
从血友病 B 疾病突变中生物物理拯救凝血因子 IXa 构象整体
  • 批准号:
    9132043
  • 财政年份:
    2015
  • 资助金额:
    $ 5.92万
  • 项目类别:

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