Detailed Information on Publication Record

JANOŠ, Pavel, Stanislav KOZMON, Igor TVAROŠKA and Jaroslav KOČA. Three-dimensional homology model of GlcNAc-TV glycosyltransferase. Glycobiology. Oxford University Press, 2016, vol. 26, No 7, p. 757-771. ISSN 0959-6658. Available from: https://dx.doi.org/10.1093/glycob/cww010.

Other formats: BibTeX LaTeX RIS

Basic information
Original name	Three-dimensional homology model of GlcNAc-TV glycosyltransferase
Authors	JANOŠ, Pavel (203 Czech Republic, belonging to the institution), Stanislav KOZMON (703 Slovakia, belonging to the institution), Igor TVAROŠKA (703 Slovakia, belonging to the institution) and Jaroslav KOČA (203 Czech Republic, guarantor, belonging to the institution).
Edition	Glycobiology, Oxford University Press, 2016, 0959-6658.

Other information
Original language	English
Type of outcome	Article in a journal
Field of Study	10600 1.6 Biological sciences
Country of publisher	United States of America
Confidentiality degree	is not subject to a state or trade secret
WWW	URL
Impact factor	Impact factor: 3.112
RIV identification code	RIV/00216224:14310/16:00089828
Organization unit	Faculty of Science
Doi	http://dx.doi.org/10.1093/glycob/cww010
UT WoS	000384766000009
Keywords in English	GlcNAc-TV; glycosyltransferase; homology model; N-glycosylation
Tags	AKR, rivok
Tags	International impact, Reviewed
Changed by	Changed by: Ing. Andrea Mikešková, učo 137293. Changed: 14/4/2017 16:00.

Abstract
The enzyme UDP-N-acetylglucosamine: a-d-mannoside b-1-6 N-acetylglucosaminyltransferase V (GnT-V) catalyzes the transfer of GlcNAc from the UDP-GlcNAc donor to the a-1-6-linked mannose of the trimannosyl core structure of glycoproteins to produce the b-1-6-linked branching of N-linked oligosaccharides. b-1-6-GlcNAc-branched N-glycans are associated with cancer growth and metastasis. Therefore, the inhibition of GnT-V represents a key target for anti-cancer drug development. However, the development of potent and specific inhibitors of GnT-V is hampered by the lack of information on the three-dimensional structure of the enzyme and on the binding characteristics of its substrates. Here we present the first 3D structure of GnT-V as a result of homology modeling. Various alignment methods, docking the donor and acceptor substrates, and molecular dynamics simulation were used to construct seven homology models of GnT-V and characterize the binding of its substrates. The best homology model is consistent with available experimental data. The three-dimensional model, the structure of the enzyme catalytic site and binding information obtained for the donor and acceptor can be useful in studies of the catalytic mechanism and design of inhibitors of GnT-V.

Abstract

The enzyme UDP-N-acetylglucosamine: a-d-mannoside b-1-6 N-acetylglucosaminyltransferase V (GnT-V) catalyzes the transfer of GlcNAc from the UDP-GlcNAc donor to the a-1-6-linked mannose of the trimannosyl core structure of glycoproteins to produce the b-1-6-linked branching of N-linked oligosaccharides. b-1-6-GlcNAc-branched N-glycans are associated with cancer growth and metastasis. Therefore, the inhibition of GnT-V represents a key target for anti-cancer drug development. However, the development of potent and specific inhibitors of GnT-V is hampered by the lack of information on the three-dimensional structure of the enzyme and on the binding characteristics of its substrates. Here we present the first 3D structure of GnT-V as a result of homology modeling. Various alignment methods, docking the donor and acceptor substrates, and molecular dynamics simulation were used to construct seven homology models of GnT-V and characterize the binding of its substrates. The best homology model is consistent with available experimental data. The three-dimensional model, the structure of the enzyme catalytic site and binding information obtained for the donor and acceptor can be useful in studies of the catalytic mechanism and design of inhibitors of GnT-V.

Links
ED1.1.00/02.0068, research and development project	Name: CEITEC - central european institute of technology
LH13055, research and development project	Name: Multidisciplinární přístup k návrhu léčiv - Inhibice proteinů s návazností na cukry (Acronym: MADICA)
LH13055, research and development project	Investor: Ministry of Education, Youth and Sports of the CR