CATALYTIC ANTIBODY DESIGN & CHARACTERIZATION

催化抗体设计

基本信息

项目摘要

In a project aimed at understanding basic structure-function relations in enzymatic catalysis, we have created a new family of enzyme-like catalysts from an immunoglobulin molecules. Our two most active catalytic antibodies, 17E8 and 29G11, prepared through immunization with a norleucine phenyl phosphonate transition state analog, and catalyze the hydrolysis norleucine phenyl ester substrates. These catalytic antibodies are fairly efficient esterases. Preliminary mechanistic experiments suggest that 17E8 esterolysis proceeds through the formation of a covalent acyl-enzyme intermediate in analogy to the serine proteases, whereas 29G11 esterolysis involves direct attack of water at the substrate carbonyl group. In a collaboration with Robert Fletterick's group we have solved the crystal structure of the 17E8-1 complex. The structure reveals a remarkable similarity between the active site of 17E8 and active sites of natural triad-based hydrolases such as the serine proteases and acetyl cholinesterase. The 17E8 active site contains a Ser-His catalytic dyad instead of the Ser-His-Asp catalytic triad of the natural hydrolases. In addition, the 17E8 active site features a protonated Lys side chain which we believe functions as an "oxyanion hole" equivalent to stabilize the development of oxyanion character in the hydrolytic transition state. In contrast, the natural hydrolases accommodate oxyanion stabilization with H-bonding interactions from backbone amide NH groups. Together the data suggest a hydrolytic mechanism similar to the natural enzymes involving nucleophilic attack by the active site Ser. We are currently testing this hypothesis with mechanistic probes, site-directed mutagenesis, and further structural characterization.
在一个旨在了解基本结构功能的项目中

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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THOMAS Sterling SCANLAN其他文献

THOMAS Sterling SCANLAN的其他文献

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{{ truncateString('THOMAS Sterling SCANLAN', 18)}}的其他基金

Chemical Biology Studies of 3-Iodothyronamine and Related Thyroid Hormone Metabol
3-碘甲腺胺及相关甲状腺激素代谢的化学生物学研究
  • 批准号:
    8235583
  • 财政年份:
    2012
  • 资助金额:
    $ 27.32万
  • 项目类别:
Chemical Biology Studies of 3-Iodothyronamine and Related Thyroid Hormone Metabol
3-碘甲腺胺及相关甲状腺激素代谢的化学生物学研究
  • 批准号:
    8464697
  • 财政年份:
    2012
  • 资助金额:
    $ 27.32万
  • 项目类别:
Chemical Biology Studies of 3-Iodothyronamine and Related Thyroid Hormone Metabol
3-碘甲腺胺及相关甲状腺激素代谢的化学生物学研究
  • 批准号:
    8665414
  • 财政年份:
    2012
  • 资助金额:
    $ 27.32万
  • 项目类别:
STRUCTURE & MECHANISM OF HYDROLYTIC ANTIBODIES
结构
  • 批准号:
    7601805
  • 财政年份:
    2007
  • 资助金额:
    $ 27.32万
  • 项目类别:
STRUCTURE & MECHANISM OF HYDROLYTIC ANTIBODIES
结构
  • 批准号:
    7369025
  • 财政年份:
    2006
  • 资助金额:
    $ 27.32万
  • 项目类别:
STRUCTURE & MECHANISM OF HYDROLYTIC ANTIBODIES
结构
  • 批准号:
    7180908
  • 财政年份:
    2005
  • 资助金额:
    $ 27.32万
  • 项目类别:
STRUCTURE & MECHANISM OF HYDROLYTIC ANTIBODIES
结构
  • 批准号:
    6976595
  • 财政年份:
    2004
  • 资助金额:
    $ 27.32万
  • 项目类别:
LIGAND PHARMACOLOGY OF ESTROGEN RECEPTORS
雌激素受体的配体药理学
  • 批准号:
    6381790
  • 财政年份:
    2000
  • 资助金额:
    $ 27.32万
  • 项目类别:
LIGAND PHARMACOLOGY OF ESTROGEN RECEPTORS
雌激素受体的配体药理学
  • 批准号:
    6517731
  • 财政年份:
    2000
  • 资助金额:
    $ 27.32万
  • 项目类别:
STRUCTURE & MECHANISM OF HYDROLYTIC ANTIBODIES
结构
  • 批准号:
    6308885
  • 财政年份:
    2000
  • 资助金额:
    $ 27.32万
  • 项目类别:

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