Molecular and Structural Studies of Antibody Diversity Mechanisms
抗体多样性机制的分子和结构研究
基本信息
- 批准号:8631926
- 负责人:
- 金额:$ 36.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-30 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAmino AcidsAntibodiesAntibody DiversityAntigensArchitectureBindingCattleColorCrystallographyDataDiagnosticDisulfidesEngineeringFlow CytometryGeneticImmunoglobulin DomainImmunoglobulinsKnowledgeLeadLibrariesMammalsMedicalModelingMolecularMutagenesisPatternPeptidesPharmaceutical PreparationsPhylogenyProcessPropertyProtein EngineeringProteinsResearchRoleStructureSurface ImmunoglobulinsSystemTherapeuticVariantantibody engineeringantigen bindingdeep sequencingdisulfide bonddrug developmentnovelphysical propertypublic health relevanceresearch studyscaffold
项目摘要
Abstract
Antibody molecules are enormously important as therapeutic and diagnostic molecules. More
recently, unique scaffolds like the VHH of camelids, or even non-antibody frameworks like
"knottins" have become important in biomedicine. Antibody diversity and antigen binding in
mammals is often restricted to the CDR loops of the immunoglobulin fold. In experiments
challenging this paradigm, we have recently solved the crystal structures of two bovine
antibodies containing ultralong CDR H3s (56 and 61 amino acids) and also deep sequenced
the ultralong repertoire. Our data reveal that these CDR H3s form a very unusual architecture
composed of a long b-strand "stalk" which supports a disulfide rich "knob" that protrudes far
from the immunoglobulin surface. Interestingly, the two different antibodies contain different
patterns of disulfides, which result in different knob structures. Deep sequencing reveals
extensive diversity in the ultralong CDR H3s where a multitude of different disulfides could
potentially form within the knob. Thus, the bovine antibody system can produce an
unprecedented repertoire of mega CDR H3s that may result in an impressive diversity of
minifolds containing combinations of somatically generated disulfides. Thus, antibody diversity
is located in a new minifold supported by the immunoglobulin domain. We will perform
structural, functional, and engineering studies to investigate the properties of this new antibody
class, as well as to lead the way to developing this unique structure into therapeutics.
摘要
抗体分子作为治疗和诊断分子非常重要。更
最近,独特的支架,如骆驼科动物的VHH,甚至是非抗体框架,
“结蛋白”在生物医学中变得重要。抗体多样性和抗原结合
在哺乳动物中,免疫球蛋白的CDR环通常限于免疫球蛋白折叠的CDR环。在实验中
挑战这种模式,我们最近解决了两个牛的晶体结构,
含有超长CDR H3(56和61个氨基酸)的抗体,
超长曲目我们的数据显示,这些CDR H3形成了一种非常不寻常的结构,
由一个长的b股“茎”组成,它支持一个突出很远的富含二硫化物的“球”,
从免疫球蛋白表面。有趣的是,这两种不同的抗体含有不同的
二硫化物的模式,这导致不同的旋钮结构。深度测序揭示
超长CDR H3的广泛多样性,其中多种不同的二硫化物可以
可能在旋钮内形成。因此,牛抗体系统可以产生
前所未有的大型CDR H3库,可能会导致令人印象深刻的多样性,
含有体细胞产生的二硫化物的组合的微折叠。因此,抗体多样性
位于由免疫球蛋白结构域支持的新微折叠中。我们将执行
结构,功能和工程研究,以研究这种新抗体的特性
类,以及领导的方式,以发展这种独特的结构到治疗。
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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PETER G SCHULTZ其他文献
PETER G SCHULTZ的其他文献
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{{ truncateString('PETER G SCHULTZ', 18)}}的其他基金
Synthesis at the Interface of Chemistry and Biology
化学与生物学交叉点的合成
- 批准号:
10596163 - 财政年份:2022
- 资助金额:
$ 36.01万 - 项目类别:
Synthesis at the Interface of Chemistry and Biology
化学与生物学交叉点的合成
- 批准号:
10406629 - 财政年份:2022
- 资助金额:
$ 36.01万 - 项目类别:
Experimentally Testing the Endosymbiotic Theory of Mitochondrial Evolution
实验检验线粒体进化的内共生理论
- 批准号:
9904721 - 财政年份:2019
- 资助金额:
$ 36.01万 - 项目类别:
An Orally Bioavailable Drug Candidate for Spinal Muscular Atrophy
一种治疗脊髓性肌萎缩症的口服生物利用候选药物
- 批准号:
9005317 - 财政年份:2016
- 资助金额:
$ 36.01万 - 项目类别:
Molecular and Structural Studies of Antibody Diversity Mechanisms
抗体多样性机制的分子和结构研究
- 批准号:
8930163 - 财政年份:2014
- 资助金额:
$ 36.01万 - 项目类别:
Ribosomal Synthesis of Peptides with Unnatural Building Blocks
具有非天然结构单元的肽的核糖体合成
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8082393 - 财政年份:2011
- 资助金额:
$ 36.01万 - 项目类别:
Ribosomal Synthesis of Peptides with Unnatural Building Blocks
具有非天然结构单元的肽的核糖体合成
- 批准号:
8412755 - 财政年份:2011
- 资助金额:
$ 36.01万 - 项目类别:
Ribosomal Synthesis of Peptides with Unnatural Building Blocks
具有非天然结构单元的肽的核糖体合成
- 批准号:
8268133 - 财政年份:2011
- 资助金额:
$ 36.01万 - 项目类别:
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