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Structure-based redesign methods to ...

Sleiman Haidar, Jaafar Nassar.

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Structure-based redesign methods to enhance the binding affinity of the TCR/PEP-MHC interface.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Structure-based redesign methods to enhance the binding affinity of the TCR/PEP-MHC interface./
作者:	Sleiman Haidar, Jaafar Nassar.
面頁冊數:	130 p.
附註:	Adviser: Zhiping Weng.
Contained By:	Dissertation Abstracts International68-08B.
標題:	Biology, Bioinformatics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3279964
ISBN:	9780549212393

Structure-based redesign methods to enhance the binding affinity of the TCR/PEP-MHC interface.
Sleiman Haidar, Jaafar Nassar.

Structure-based redesign methods to enhance the binding affinity of the TCR/PEP-MHC interface. - 130 p.

Adviser: Zhiping Weng.

Thesis (Ph.D.)--Boston University, 2008.

Due to their essential role in the immune system, complexes of the immunoglobulin superfamily (IgSF) have become the focus of therapeutic development and diagnostic applications. Manipulating the stability and the specificity of the IgSF interfaces is elemental to their biomedical and clinical applications. In particular, enhancing the affinity of the T-cell receptor (TCR, KD&sim;muM) to the peptide-MHC complex enables us to utilize this immunoglobulin as a sensor to diagnose and treat invaded tissue more efficiently. In this study, I developed different structure-based methods to predict single mutations that boost the sensitivity of the TCR to the peptide-MHC complex. These predictions were experimentally validated via surface plasmon resonance (SPR) to determine their binding affinities to the peptide-MHC.

ISBN: 9780549212393Subjects--Topical Terms:

1018415
Biology, Bioinformatics.

Structure-based redesign methods to enhance the binding affinity of the TCR/PEP-MHC interface.
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100 1 $a Sleiman Haidar, Jaafar Nassar. $3 1263067
245 1 0 $a Structure-based redesign methods to enhance the binding affinity of the TCR/PEP-MHC interface.
300 $a 130 p.
500 $a Adviser: Zhiping Weng.
500 $a Source: Dissertation Abstracts International, Volume: 68-08, Section: B, page: 5396.
502 $a Thesis (Ph.D.)--Boston University, 2008.
520 $a Due to their essential role in the immune system, complexes of the immunoglobulin superfamily (IgSF) have become the focus of therapeutic development and diagnostic applications. Manipulating the stability and the specificity of the IgSF interfaces is elemental to their biomedical and clinical applications. In particular, enhancing the affinity of the T-cell receptor (TCR, KD&sim;muM) to the peptide-MHC complex enables us to utilize this immunoglobulin as a sensor to diagnose and treat invaded tissue more efficiently. In this study, I developed different structure-based methods to predict single mutations that boost the sensitivity of the TCR to the peptide-MHC complex. These predictions were experimentally validated via surface plasmon resonance (SPR) to determine their binding affinities to the peptide-MHC.
520 $a This study discusses the details of developing, optimizing and testing an accurate and simple scoring function that we call Zaffi. Zaffi computes the binding DeltaDeltaG from bound modeled structures of TCR single point mutations. The computed binding DeltaDeltaGs of this target function correlate highly (r = 0.85) with the experimentally determined binding DeltaDeltaGs of the TCR single point mutations. 73% of Zaffi's single point mutations improve the stability of the TCR/peptide-MHC interaction. Upon accumulating different single point mutations predicted by Zaffi, a quadruple TCR mutant augmented the binding affinity of this complex by 111 folds. Currently, this is the highest computationally redesigned affinity enhancement of the TCR/peptide-MHC.
520 $a Additionally, this study discusses a mutational strategy that will decrease the loss of entropy in the backbone during the TCR/peptide-MHC complex formation. Prolines were systematically introduced to the TCR CDRs in order to further stabilize the TCR/peptide-MHC complex. SPR experiments showed that two of the proline substitutions improved the stability of the complex by increasing its binding association rate. One of the two substitutions improved the stability of the complex by 20 folds. When combining this mutation with Zaffi 's quadruple variant, the affinity of the complex was boosted to the nM range. In conclusion, structure-based interface design can be successfully implemented to perform affinity maturation of the IgSF interfaces.
590 $a School code: 0017.
650 4 $a Biology, Bioinformatics. $3 1018415
650 4 $a Biophysics, General. $3 1019105
650 4 $a Engineering, Biomedical. $3 1017684
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710 2 $a Boston University. $3 1017454
773 0 $t Dissertation Abstracts International $g 68-08B.
790 $a 0017
790 1 0 $a Weng, Zhiping, $e advisor
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3279964