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    Structure of the farnesoid X receptor ligand binding domain and methods of use therefor
    1.
    发明授权
    Structure of the farnesoid X receptor ligand binding domain and methods of use therefor 失效
    法呢酯X受体配体结合域的结构及其用途

    公开(公告)号：US07647217B2

    公开(公告)日：2010-01-12

    申请号：US10535042

    申请日：2003-11-14

    申请人： Michael R Downes ,  Mark A. Verdicia ,  Joseph P. Noel ,  Ronald M. Evans ,  Lindsey J. Bowman ,  Marianne Bowman

    发明人： Michael R Downes ,  Mark A. Verdicia ,  Joseph P. Noel ,  Ronald M. Evans ,  Lindsey J. Bowman ,  Marianne Bowman

    IPC分类号： G06G7/58 ,  C07K14/00

    CPC分类号： C07K14/70567 ,  C07K2299/00 ,  G01N33/743 ,  G01N2500/00 ,  G06F19/16 ,  G06F19/706

    摘要： The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist, fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a three-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.

    摘要翻译： 本发明提供了包含结晶形式的法呢甾X受体（FXR）的配体结合结构域（LBD）的组合物。 在替代实施方案中，FXR的LBD与其配体复合。 提供了与新型高亲和力激动剂fexaramine复合的FXR的高分辨率结构。 所发现的FXR LBD的结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明还提供一种用于产生FXR或其复数的三维表示的计算机，以及用于确定FXR的结构坐标的至少一部分或其复合体的计算机。 本发明还提供使用该结构信息来预测能够结合FXR的分子的方法; 识别FXR激动剂，拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明还提供包含通过本发明方法鉴定的化合物的组合物。

    Structure of the farnesoid X receptor ligand binding domain and methods of use therefor
    2.
    发明授权
    Structure of the farnesoid X receptor ligand binding domain and methods of use therefor 失效
    法呢酯X受体配体结合域的结构及其用途

    公开(公告)号：US08212006B2

    公开(公告)日：2012-07-03

    申请号：US12686347

    申请日：2010-01-12

    申请人： Michael R. Downes ,  Mark A. Verdicia ,  Joseph P. Noel ,  Ronald M. Evans ,  Lindsey J. Bowman ,  Marianne Bowman

    发明人： Michael R. Downes ,  Mark A. Verdicia ,  Joseph P. Noel ,  Ronald M. Evans ,  Lindsey J. Bowman ,  Marianne Bowman

    IPC分类号： C07K1/00 ,  G06G7/58 ,  A01N61/00

    CPC分类号： C07K14/70567 ,  C07K2299/00 ,  G01N33/743 ,  G01N2500/00 ,  G06F19/16 ,  G06F19/706

    摘要： The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a time-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.

    摘要翻译： 本发明提供了包含结晶形式的法呢甾X受体（FXR）的配体结合结构域（LBD）的组合物。 在替代实施方案中，FXR的LBD与其配体复合。 提供了与新型高亲和力激动剂福沙康胺复合的FXR的高分辨率结构。 所发现的FXR LBD的结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明还提供一种用于产生FXR或其复数的时间维度表示的计算机，以及用于确定FXR或其复数的结构坐标的至少一部分的计算机。 本发明还提供使用该结构信息来预测能够结合FXR的分子的方法; 识别FXR激动剂，拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明还提供包含通过本发明方法鉴定的化合物的组合物。

    STRUCTURE OF THE FARNESOID X RECEPTOR LIGAND BINDING DOMAIN AND METHODS OF USE THEREFOR
    3.
    发明申请
    STRUCTURE OF THE FARNESOID X RECEPTOR LIGAND BINDING DOMAIN AND METHODS OF USE THEREFOR 失效
    FARNESOID X受体配体结合域的结构及其使用方法

    公开(公告)号：US20110018866A1

    公开(公告)日：2011-01-27

    申请号：US12686347

    申请日：2010-01-12

    申请人： Michael R. Downes ,  Mark A. Verdicia ,  Joseph P. Noel ,  Ronald M. Evans ,  Lindsey J. Bowman ,  Marianne Bowman

    发明人： Michael R. Downes ,  Mark A. Verdicia ,  Joseph P. Noel ,  Ronald M. Evans ,  Lindsey J. Bowman ,  Marianne Bowman

    IPC分类号： C07C229/44 ,  C07K14/72 ,  A61K38/16 ,  A61K31/216 ,  C07D317/58 ,  A61K31/36 ,  C07J9/00 ,  A61K31/575 ,  C07D261/08 ,  A61K31/42 ,  G06G7/58 ,  G06T15/00

    CPC分类号： C07K14/70567 ,  C07K2299/00 ,  G01N33/743 ,  G01N2500/00 ,  G06F19/16 ,  G06F19/706

    摘要： The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a time-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR. The present invention further provides compositions comprising compounds identified by such invention methods.

    摘要翻译： 本发明提供了包含结晶形式的法呢甾X受体（FXR）的配体结合结构域（LBD）的组合物。 在替代实施方案中，FXR的LBD与其配体复合。 提供了与新型高亲和力激动剂福沙康胺复合的FXR的高分辨率结构。 所发现的FXR LBD的结构提供了FXR配体结合的结构基础的第一个三维视图。 本发明还提供一种用于产生FXR或其复数的时间维度表示的计算机，以及用于确定FXR或其复数的结构坐标的至少一部分的计算机。 本发明还提供使用该结构信息来预测能够结合FXR的分子的方法; 识别FXR激动剂，拮抗剂或部分激动剂活性的化合物; 并确定测试化合物是否能够结合FXR的LBD。 本发明还提供包含通过本发明方法鉴定的化合物的组合物。

    SMRT co-repressors, transcriptional co-repressors that interact with nuclear hormone receptors
    4.
    发明授权
    SMRT co-repressors, transcriptional co-repressors that interact with nuclear hormone receptors 失效
    SMRT共同抑制因子，与核激素受体相互作用的转录共抑制因子

    公开(公告)号：US07314747B1

    公开(公告)日：2008-01-01

    申请号：US09522753

    申请日：2000-03-10

    申请人： Ronald M. Evans ,  J. Don Chen ,  Peter Ordentlich ,  Michael R. Downes

    发明人： Ronald M. Evans ,  J. Don Chen ,  Peter Ordentlich ,  Michael R. Downes

    IPC分类号： C12N1/15 ,  C12N5/10 ,  C12N15/00 ,  C07H21/04

    CPC分类号： C07K14/4703 ,  G01N33/74 ,  G01N2500/00

    摘要： The present invention relates to isolated polynucleotides encoding a family of silencing mediators of retinoic acid and thyroid hormone receptor (SMRT) isoforms, including vertebrate and invertebrate isoforms thereof. The invention also relates to polypeptide SMRT co-repressors encoded by invention SMRT polynucleotides, and to peptide portions thereof that can modulate transcriptional potential of a nuclear receptor. In addition, the invention relates to chimeric molecules and to complexes containing a SMRT co-repressor or peptide portion thereof, to antibodies that specifically bind such compositions, and to methods for identifying an agent that modulates the repressor potential of a SMRT co-repressor. The invention also provides methods for identifying an agent that modulates a function of a SMRT co-repressor; for modulating the transcriptional potential of a nuclear receptor in a cell using the compositions of the invention; and for identifying a molecule that interacts specifically with a SMRT co-repressor.

    摘要翻译： 本发明涉及编码维甲酸和甲状腺激素受体（SMRT）同种型的沉默介导家族的分离多核苷酸，包括脊椎动物和无脊椎动物同种型。 本发明还涉及由本发明的SMRT多核苷酸编码的多肽SMRT共抑制子及其可调节核受体的转录潜力的肽部分。 此外，本发明涉及嵌合分子和含有SMRT共抑制子或其肽部分的复合物与特异性结合该组合物的抗体以及用于鉴定调节SMRT共抑制因子的阻遏物潜力的试剂的方法。 本发明还提供了用于鉴定调节SMRT共抑制子功能的试剂的方法; 用于使用本发明的组合物调节细胞中核受体的转录电位; 并用于鉴定与SMRT共抑制子特异性相互作用的分子。

    Methods of Identifying Functional Characteristics of Promoters, Transcription Modifying Proteins and Transcription Modulating Agents
    8.
    发明申请
    Methods of Identifying Functional Characteristics of Promoters, Transcription Modifying Proteins and Transcription Modulating Agents 审中-公开
    鉴定启动子，转录修饰蛋白和转录调节剂功能特征的方法

    公开(公告)号：US20110263454A1

    公开(公告)日：2011-10-27

    申请号：US13061500

    申请日：2009-08-28

    申请人： Johan W. Jonker ,  Michael Downes ,  Ronald M. Evans

    发明人： Johan W. Jonker ,  Michael Downes ,  Ronald M. Evans

    IPC分类号： C40B30/06 ,  C40B60/12

    CPC分类号： C12Q1/6897 ,  C12N15/1086

    摘要： Provided herein is, inter alia, methods and compositions useful in therapeutic interrogation of complex physiologic pathways by massively parallel and permissive transcriptional screening. Thus, methods and compositions are provided herein that are useful for high-throughput functional analysis of complex, transcriptionally regulated physiological pathways. While examples are provided relating to nuclear receptors, the methods and composition can be generalized and applied to any class of transcription factor or any class of gene product that can regulate the activity of transcription. For example, in addition to nuclear receptors, the methods and compositions provided herein are generally applicable to all known transcription factors and any gene encoded product that modulates said transcription factor activity. Moreover, data obtained through the methods provided herein are directly comparable thereby facilitating high-throughput functional analysis.

    摘要翻译： 本文提供了通过大规模平行和允许的转录筛选在治疗性询问复杂生理学途径中有用的方法和组合物。 因此，本文提供了可用于复杂的转录调节生理学途径的高通量功能分析的方法和组合物。 虽然提供了与核受体相关的实例，但是该方法和组成可以被推广并应用于可以调节转录活性的任何类型的转录因子或任何类型的基因产物。 例如，除了核受体之外，本文提供的方法和组合物通常可应用于调节所述转录因子活性的所有已知转录因子和任何基因编码产物。 此外，通过本文提供的方法获得的数据是直接可比的，因此有助于高通量功能分析。

    Response element compositions and assays employing same
    10.
    发明授权
    Response element compositions and assays employing same 失效
    响应元素组合物和采用其的测定法

    公开(公告)号：US07189510B2

    公开(公告)日：2007-03-13

    申请号：US10302557

    申请日：2002-11-22

    申请人： Henry M. Sucov ,  Ronald M. Evans ,  Kazuhiko Umesono

    发明人： Henry M. Sucov ,  Ronald M. Evans ,  Kazuhiko Umesono

    IPC分类号： C12Q1/68

    CPC分类号： C07K14/70567 ,  C07K14/721 ,  C12N15/85 ,  C12N2800/108 ,  C12N2830/002 ,  C12N2830/008 ,  C12N2830/30 ,  C12N2830/38 ,  C12N2830/60 ,  C12N2830/85 ,  C12Q1/6897 ,  G01N33/5008 ,  G01N33/502 ,  G01N33/5023 ,  G01N33/5041 ,  G01N33/743

    摘要： DNA segments have been discovered, and characterized by sequence, which are response elements operative to confer responsiveness to ligands for several members of the steroid/thyroid superfamily of receptors, for the transcriptional activation and/or repression of promoters in cells. By using transcriptional control regions comprising response elements of the present invention in combination with a functional promoter, it is now possible to provide recombinant DNA vectors containing a gene, the transcription (and, thereby, also expression) of which is under the control of a promoter, the transcriptional activity of which is responsive to ligands for members of the steroid/thyroid superfamily of receptors.

    摘要翻译： 已经发现了DNA区段，其特征在于序列，其是作用于赋予类固醇/甲状腺超家族受体的若干成员对配体的反应性的响应元件，用于细胞中启动子的转录激活和/或抑制。 通过使用包含本发明的响应元件与功能启动子组合的转录控制区，现在可以提供含有基因的重组DNA载体，其转录（并且由此也由其表达）处于一个 启动子，其转录活性对受体的类固醇/甲状腺超家族成员的配体有反应。