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I. X-ray crystal structure of the Mu...

Hu, Yanan.

I. X-ray crystal structure of the MurG:UDP-GlcNAc cocomplex. II. High throughput screening of Escherichia coli MurG.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	I. X-ray crystal structure of the MurG:UDP-GlcNAc cocomplex. II. High throughput screening of Escherichia coli MurG.
作者:	Hu, Yanan.
面頁冊數:	152 p.
附註:	Adviser: Suzanne Walker.
附註:	Source: Dissertation Abstracts International, Volume: 65-06, Section: B, page: 2920.
Contained By:	Dissertation Abstracts International65-06B.
標題:	Chemistry, Biochemistry.
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3135740
ISBN:	0496829556

I. X-ray crystal structure of the MurG:UDP-GlcNAc cocomplex. II. High throughput screening of Escherichia coli MurG.
Hu, Yanan.

I. X-ray crystal structure of the MurG:UDP-GlcNAc cocomplex. II. High throughput screening of Escherichia coli MurG. - 152 p.

Adviser: Suzanne Walker.

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

Glycosyltransferases play key roles in a wide range of biological processes, many of which are not well understood. MurG is an essential glycosyltransferase that forms the glycosidic linkage between N-acetyl muramyl pentapeptide and N-acetyl glucosamine in the biosynthesis of the bacterial cell wall. The crystal structure of the free enzyme combined with sequence data on other glycosyltransferases revealed that MurG is a paradigm for a major superfamily of NDP-glycosyltransferases. Prior to this thesis work, no x-ray structures of any members of this glycosyltransferase superfamily containing intact donor substrates had been reported.

ISBN: 0496829556Subjects--Topical Terms:

226900
Chemistry, Biochemistry.

I. X-ray crystal structure of the MurG:UDP-GlcNAc cocomplex. II. High throughput screening of Escherichia coli MurG.
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245 1 0 $a I. X-ray crystal structure of the MurG:UDP-GlcNAc cocomplex. II. High throughput screening of Escherichia coli MurG.
300 $a 152 p.
500 $a Adviser: Suzanne Walker.
500 $a Source: Dissertation Abstracts International, Volume: 65-06, Section: B, page: 2920.
502 $a Thesis (Ph.D.)--Princeton University, 2004.
520 # $a Glycosyltransferases play key roles in a wide range of biological processes, many of which are not well understood. MurG is an essential glycosyltransferase that forms the glycosidic linkage between N-acetyl muramyl pentapeptide and N-acetyl glucosamine in the biosynthesis of the bacterial cell wall. The crystal structure of the free enzyme combined with sequence data on other glycosyltransferases revealed that MurG is a paradigm for a major superfamily of NDP-glycosyltransferases. Prior to this thesis work, no x-ray structures of any members of this glycosyltransferase superfamily containing intact donor substrates had been reported.
520 # $a The MurG enzyme is conserved in almost all bacteria, and inhibitors will allow us to explore its potential as an antibiotic target. In addition, the ability to block glycosyltransferases will be useful for probing the biological roles of glycosyltransferases and their products. However, few selective glycosyltransferase inhibitors exist and it is not yet clear how one might proceed in developing such inhibitors. We have explored the utility of a high-throughput screen based upon displacement of a fluorescent glycosyl donor to discover inhibitors for MurG using the structure information. This donor displacement assay enabled us to screen large numbers of compounds rapidly, and we have shown here that several compounds identified from a donor displacement screen of MurG are selective for MurG over closely related enzymes that use similar or identical substrates. This high throughput screening strategy can be adapted to screen other glycosyltransferases, and represents a general strategy to identify selective small molecule inhibitors of glycosyltransferases.
520 # $a We successfully obtained MurG:UDP-GlcNAc crystals and solved the structure of the cocomplex at 2.5 A using the molecular replacement method. The structure of the MurG:UDP-GlcNAc complex sheds light on a major superfamily of glycosyltransferases and provides insight into the origins of substrate selectivity as well as how catalytic efficiency might be improved for some family members. By comparing structures and sequences of different family members, it is possible to identify the regions that determine selectivity. It should be possible to alter those regions to achieve new selectivities and/or to relax the existing selectivity.
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