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Genome-wide chemical genetic analysi...

Zhang, Chao.

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Genome-wide chemical genetic analysis of protein kinases.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Genome-wide chemical genetic analysis of protein kinases./
Author:	Zhang, Chao.
Description:	150 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4954.
Contained By:	Dissertation Abstracts International64-10B.
Subject:	Chemistry, Organic. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3107885
ISBN:	0496554336

Genome-wide chemical genetic analysis of protein kinases.
Zhang, Chao.

Genome-wide chemical genetic analysis of protein kinases. - 150 p.

Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4954.

Thesis (Ph.D.)--Princeton University, 2004.

The large number of protein kinases and the high homology in the protein kinase superfamily make it difficult to deconvolute the roles of individual protein kinases in eukaryotic signaling networks. To facilitate the study of protein kinases, our laboratory has developed a chemical genetic approach, which involves mutating a key residue in the kinase active site to sensitize the kinase to analogs of ATP or an inhibitor. Despite its general success, two problems were encountered when the approach was applied to a wide variety of kinases. Some analog-sensitized kinases exhibited low enzymatic activity while others were poorly inhibited by the existing analogs of PP1.

ISBN: 0496554336Subjects--Topical Terms:

516206
Chemistry, Organic.

Genome-wide chemical genetic analysis of protein kinases.
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100 1 $a Zhang, Chao. $3 1620564
245 1 0 $a Genome-wide chemical genetic analysis of protein kinases.
300 $a 150 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-10, Section: B, page: 4954.
500 $a Adviser: Kevan Shokat.
502 $a Thesis (Ph.D.)--Princeton University, 2004.
520 $a The large number of protein kinases and the high homology in the protein kinase superfamily make it difficult to deconvolute the roles of individual protein kinases in eukaryotic signaling networks. To facilitate the study of protein kinases, our laboratory has developed a chemical genetic approach, which involves mutating a key residue in the kinase active site to sensitize the kinase to analogs of ATP or an inhibitor. Despite its general success, two problems were encountered when the approach was applied to a wide variety of kinases. Some analog-sensitized kinases exhibited low enzymatic activity while others were poorly inhibited by the existing analogs of PP1.
520 $a Described in this thesis are several approaches we investigated to address these two problems associated with the analog-sensitized kinases. By screening a mutant library, second-site suppressor mutations were identified for an aminoglycoside kinase (APH), which was employed as a model of eukaryotic protein kinases. Some of the suppressor mutations are located in the kinase N-terminal lobe and seem to exert their effect by stabilizing a beta sheet. Realizing the importance of beta sheet stability to the kinase activity, a structure-based sequence alignment that includes many residues within the beta sheet was created. Through analysis of the alignment, second-site suppressor mutations were rationally identified for kinases including MEKK1, CDC5 and GRK2.
520 $a To address the problem of poor inhibition, a series of purine derivatives were designed and synthesized as inhibitors for analog-sensitized kinases. These disubstituted purines exhibited potent inhibitory activity toward a broad range of kinases. In addition, a new series of PP1 analogs with small substituents was synthesized, some of which exhibited significant improvement at inhibiting kinases including Bur1 and Akt1.
520 $a Finally, a chemical genetic approach that generates allele-specific irreversible inhibitors for protein kinases was developed. This approach involves engineering a nucleophilic cysteine residue into the kinase active site to react with an electrophilic PP1 analog. It was demonstrated that electrophilic inhibitors generated using this approach are both potent and selective toward engineered kinases. The new approach holds high promise to be used to complement the original approach in the study of protein kinases.
590 $a School code: 0181.
650 4 $a Chemistry, Organic. $3 516206
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773 0 $t Dissertation Abstracts International $g 64-10B.
790 1 0 $a Shokat, Kevan, $e advisor
790 $a 0181
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3107885