利用T细胞受体/HLA - DRB1*04分子模型预测与类风湿性关节炎相关的DR共享表位的位点特异性相互作用。
Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site-specific interactions for the DR shared epitope associated with rheumatoid arthritis.
作者信息
Penzotti J E, Nepom G T, Lybrand T P
机构信息
University of Washington, Seattle, USA.
出版信息
Arthritis Rheum. 1997 Jul;40(7):1316-26. doi: 10.1002/1529-0131(199707)40:7<1316::AID-ART17>3.0.CO;2-I.
OBJECTIVE
To use molecular modeling tools to analyze the potential structural basis for the genetic association of rheumatoid arthritis (RA) with the major histocompatibility complex (MHC) "shared epitope," a set of conserved amino acid residues in the third hypervariable region of the DRbeta chain.
METHODS
Homology model building techniques were used to construct molecular models of the arthritis-associated DRB1*0404 molecule and a T cell receptor (TCR) from T cell clone EM025, which is specific for DR4 molecules containing the shared epitope sequence. Interactive graphics techniques were used to orient the TCR on the DR molecule, guided by surface complementarity analysis.
RESULTS
The predicted TCR-MHC-peptide complex involved multiple interactions and specificity for the shared epitope. TCR residues CDR1beta D30, CDR2beta N51, and CDR3beta Q97 were positioned to potentially participate in hydrogen bond interactions with the shared epitope DRbeta residues Q70 and R71.
CONCLUSION
These results suggest a structural mechanism in which specific TCR recognition and possibly Vbeta selection are directly influenced by the disease-associated MHC polymorphisms.
目的
使用分子建模工具分析类风湿性关节炎（RA）与主要组织相容性复合体（MHC）“共享表位”之间遗传关联的潜在结构基础，“共享表位”是DRβ链第三个高变区中的一组保守氨基酸残基。
方法
采用同源建模技术构建与关节炎相关的DRB1*0404分子和来自T细胞克隆EM025的T细胞受体（TCR）的分子模型，该克隆对含有共享表位序列的DR4分子具有特异性。在表面互补性分析的指导下，使用交互式图形技术将TCR定位在DR分子上。
结果
预测的TCR-MHC-肽复合物涉及多种相互作用以及对共享表位的特异性。TCR残基CDR1β D30、CDR2β N51和CDR3β Q97的位置可能参与与共享表位DRβ残基Q70和R71的氢键相互作用。
结论
这些结果提示了一种结构机制，其中特定的TCR识别以及可能的Vβ选择直接受疾病相关的MHC多态性影响。
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