PMID- 30550897
OWN - NLM
STAT- MEDLINE
DCOM- 20191104
LR  - 20191104
IS  - 1872-8006 (Electronic)
IS  - 0304-4165 (Linking)
VI  - 1863
IP  - 3
DP  - 2019 Mar
TI  - Uridine diphosphate release mechanism in O-N-acetylglucosamine (O-GlcNAc) 
      transferase catalysis.
PG  - 609-622
LID - S0304-4165(18)30368-4 [pii]
LID - 10.1016/j.bbagen.2018.12.005 [doi]
AB  - O-linked N-acetylglucosamine transferase (OGT) is an essential enzyme that 
      catalyzes the covalent bonding of N-acetylglucosamine (GlcNAc) to the hydroxyl 
      group of a serine or threonine in the target protein. It plays an important role 
      in many important cellular physiological catalytic reactions. Here, we determine 
      the binding mode and the binding free energy of the OGT product (uridine 
      diphosphate, UDP) as well as the hydrogen-bond-dependent release mechanism using 
      extensive molecular dynamic simulations. The Lys634, Asn838, Gln839, Lys842, 
      His901, and Asp925 residues were identified to play a major role in the UDP 
      stabilization in the active site of OGT, where hydrogen bonding and pi-pi 
      interactions mainly occur. The calculations on the mutant forms support our 
      results. Sixteen possible release channels were identified while the two most 
      favorable channels were determined using random acceleration molecular dynamics 
      (RAMD) simulations combined with the constant velocity pulling (PCV) method. The 
      thermodynamic and dynamic properties as along with the corresponding mechanism 
      were determined and discussed according to the umbrella sampling technique. For 
      the most optimal channel, the main free energy barrier is 13 kcal/mol, which 
      probably originates from the hydrogen bonds between UDP and the Ala896 and Asp925 
      residues. Moreover, the unstable hydrogen bonds and the rollback of the ligand 
      likely cause the other two small obstacles. This work clarifies the ligand 
      transport mechanism in the OGT enzymatic process and is a great resource for 
      designing inhibitors based on UDP or UDP-GlcNAc.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - She, Nai
AU  - She N
AD  - The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, 
      Kaifeng 475004, China.
FAU - Zhao, Yuan
AU  - Zhao Y
AD  - The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, 
      Kaifeng 475004, China. Electronic address: zhaoyuan@henu.edu.cn.
FAU - Hao, Jingjing
AU  - Hao J
AD  - People's Hospital of Kaifeng, Kaifeng 475004, China.
FAU - Xie, Songqiang
AU  - Xie S
AD  - Pharmaceutical College, Henan University, Kaifeng 475004, China.
FAU - Wang, Chaojie
AU  - Wang C
AD  - The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, 
      Kaifeng 475004, China. Electronic address: wcjsxq@henu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181211
PL  - Netherlands
TA  - Biochim Biophys Acta Gen Subj
JT  - Biochimica et biophysica acta. General subjects
JID - 101731726
RN  - 58-98-0 (Uridine Diphosphate)
RN  - EC 2.4.1.- (N-Acetylglucosaminyltransferases)
RN  - EC 2.4.1.255 (OGT protein, human)
SB  - IM
MH  - Catalysis
MH  - Catalytic Domain
MH  - Humans
MH  - Hydrogen Bonding
MH  - Models, Molecular
MH  - Molecular Dynamics Simulation
MH  - N-Acetylglucosaminyltransferases/chemistry/*metabolism
MH  - Protein Interaction Domains and Motifs
MH  - Protein Structure, Secondary
MH  - Substrate Specificity
MH  - Thermodynamics
MH  - Uridine Diphosphate/chemistry/*pharmacokinetics
OTO - NOTNLM
OT  - Molecular dynamics
OT  - O-GlcNAc transferase
OT  - Release mechanism
OT  - UDP
OT  - Umbrella sampling
EDAT- 2018/12/15 06:00
MHDA- 2019/11/05 06:00
CRDT- 2018/12/15 06:00
PHST- 2018/07/10 00:00 [received]
PHST- 2018/12/06 00:00 [revised]
PHST- 2018/12/07 00:00 [accepted]
PHST- 2018/12/15 06:00 [pubmed]
PHST- 2019/11/05 06:00 [medline]
PHST- 2018/12/15 06:00 [entrez]
AID - S0304-4165(18)30368-4 [pii]
AID - 10.1016/j.bbagen.2018.12.005 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Gen Subj. 2019 Mar;1863(3):609-622. doi: 
      10.1016/j.bbagen.2018.12.005. Epub 2018 Dec 11.