CATALYTIC ANTIBODY DESIGN & CHARACTERIZATION
催化抗体设计
基本信息
- 批准号:6456785
- 负责人:
- 金额:$ 27.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-07-01 至 2003-08-31
- 项目状态:已结题
- 来源:
- 关键词:
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)
专著数量(0)
科研奖励数量(0)
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:
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