PMID- 37241849
OWN - NLM
STAT- MEDLINE
DCOM- 20230529
LR  - 20230530
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 28
IP  - 10
DP  - 2023 May 15
TI  - Binding and Dynamics Demonstrate the Destabilization of Ligand Binding for the 
      S688Y Mutation in the NMDA Receptor GluN1 Subunit.
LID - 10.3390/molecules28104108 [doi]
LID - 4108
AB  - Encephalopathies are brain dysfunctions that lead to cognitive, sensory, and 
      motor development impairments. Recently, the identification of several mutations 
      within the N-methyl-D-aspartate receptor (NMDAR) have been identified as 
      significant in the etiology of this group of conditions. However, a complete 
      understanding of the underlying molecular mechanism and changes to the receptor 
      due to these mutations has been elusive. We studied the molecular mechanisms by 
      which one of the first mutations within the NMDAR GluN1 ligand binding domain, 
      Ser688Tyr, causes encephalopathies. We performed molecular docking, randomly 
      seeded molecular dynamics simulations, and binding free energy calculations to 
      determine the behavior of the two major co-agonists: glycine and D-serine, in 
      both the wild-type and S688Y receptors. We observed that the Ser688Tyr mutation 
      leads to the instability of both ligands within the ligand binding site due to 
      structural changes associated with the mutation. The binding free energy for both 
      ligands was significantly more unfavorable in the mutated receptor. These results 
      explain previously observed in vitro electrophysiological data and provide 
      detailed aspects of ligand association and its effects on receptor activity. Our 
      study provides valuable insight into the consequences of mutations within the 
      NMDAR GluN1 ligand binding domain.
FAU - Chen, Jake Zheng
AU  - Chen JZ
AUID- ORCID: 0000-0003-0607-0483
AD  - Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, 
      Camperdown, NSW 2006, Australia.
AD  - Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
FAU - Church, William Bret
AU  - Church WB
AUID- ORCID: 0000-0002-8033-5518
AD  - Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, 
      Camperdown, NSW 2006, Australia.
FAU - Bastard, Karine
AU  - Bastard K
AD  - Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, 
      Camperdown, NSW 2006, Australia.
FAU - Duff, Anthony P
AU  - Duff AP
AD  - National Deuteration Facility, Australian Nuclear Science and Technology 
      Organization, New Illawarra Road, Lucas Heights, NSW 2234, Australia.
FAU - Balle, Thomas
AU  - Balle T
AUID- ORCID: 0000-0002-0233-8350
AD  - Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, 
      Camperdown, NSW 2006, Australia.
AD  - Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia.
LA  - eng
PT  - Journal Article
DEP - 20230515
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Ligands)
SB  - IM
MH  - *Receptors, N-Methyl-D-Aspartate/genetics/metabolism
MH  - Molecular Docking Simulation
MH  - Ligands
MH  - Protein Domains
MH  - Binding Sites
MH  - Mutation
PMC - PMC10224558
OTO - NOTNLM
OT  - NMDA receptor
OT  - encephalopathies
OT  - ligand binding
OT  - membrane protein
OT  - molecular dynamics
COIS- W.B.C. declares he is a shareholder of Filamon Pty. Ltd., which owns intellectual 
      property relating to the use of small peptides and other compounds in the 
      diagnosis and treatment of human disease. Other authors declare no conflict of 
      interest.
EDAT- 2023/05/27 09:42
MHDA- 2023/05/29 06:41
PMCR- 2023/05/15
CRDT- 2023/05/27 01:25
PHST- 2023/04/05 00:00 [received]
PHST- 2023/05/10 00:00 [revised]
PHST- 2023/05/11 00:00 [accepted]
PHST- 2023/05/29 06:41 [medline]
PHST- 2023/05/27 09:42 [pubmed]
PHST- 2023/05/27 01:25 [entrez]
PHST- 2023/05/15 00:00 [pmc-release]
AID - molecules28104108 [pii]
AID - molecules-28-04108 [pii]
AID - 10.3390/molecules28104108 [doi]
PST - epublish
SO  - Molecules. 2023 May 15;28(10):4108. doi: 10.3390/molecules28104108.