PMID- 29362509
OWN - NLM
STAT- MEDLINE
DCOM- 20190401
LR  - 20191008
IS  - 1476-5470 (Electronic)
IS  - 1466-4879 (Print)
IS  - 1466-4879 (Linking)
VI  - 20
IP  - 1
DP  - 2019 Jan
TI  - Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and 
      DRB1*15:03, with implications for multiple sclerosis.
PG  - 46-55
LID - 10.1038/s41435-017-0009-5 [doi]
AB  - Binding of small molecules in the human leukocyte antigen (HLA) peptide-binding 
      groove may result in conformational changes of bound peptide and an altered 
      immune response, but previous studies have not considered a potential role for 
      endogenous metabolites. We performed virtual screening of the complete Human 
      Metabolite Database (HMDB) for docking to the multiple sclerosis (MS) susceptible 
      DRB1*15:01 allele and compared the results to the closely related yet 
      non-susceptible DRB1*15:03 allele; and assessed the potential impact on binding 
      of human myelin basic peptide (MBP). We observed higher energy scores for 
      metabolite binding to DRB1*15:01 than DRB1*15:03. Structural comparison of docked 
      metabolites with DRB1*15:01 and DRB1*15:03 complexed with MBP revealed that 
      Phenylalanine(MBP92) allows binding of metabolites in the P4 pocket of DRB1*15:01 
      but Valine(MBP89) abrogates metabolite binding in the P1 pocket. We observed 
      differences in the energy scores for binding of metabolites in the P4 pockets of 
      DRB1*15:01 vs. DRB1*15:03 suggesting stronger binding to DRB1*15:01. Our study 
      confirmed that specific, disease-associated human metabolites bind effectively 
      with the most polymorphic P4 pocket of DRB1*15:01, the primary MS susceptible 
      allele in most populations. Our results suggest that endogenous human metabolites 
      bound in specific pockets of HLA may be immunomodulatory and implicated in 
      autoimmune disease.
FAU - Misra, Maneesh K
AU  - Misra MK
AUID- ORCID: 0000-0002-3757-3326
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      CA, 94158, USA.
FAU - Damotte, Vincent
AU  - Damotte V
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      CA, 94158, USA.
FAU - Hollenbach, Jill A
AU  - Hollenbach JA
AD  - Department of Neurology, University of California San Francisco, San Francisco, 
      CA, 94158, USA. jill.hollenbach@ucsf.edu.
LA  - eng
GR  - R01 AI128775/AI/NIAID NIH HHS/United States
GR  - R01 NS102153/NS/NINDS NIH HHS/United States
GR  - U19 NS095774/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180120
PL  - England
TA  - Genes Immun
JT  - Genes and immunity
JID - 100953417
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (MBP protein, human)
RN  - 0 (Myelin Basic Protein)
SB  - IM
MH  - *Alleles
MH  - Binding Sites
MH  - HLA-DRB1 Chains/*chemistry/genetics/metabolism
MH  - Humans
MH  - *Molecular Docking Simulation
MH  - Multiple Sclerosis/*genetics
MH  - Myelin Basic Protein/metabolism
MH  - Protein Binding
PMC - PMC6054566
MID - NIHMS916446
COIS- Conflict of Interest: None to declare.
EDAT- 2018/01/25 06:00
MHDA- 2019/04/02 06:00
PMCR- 2018/07/20
CRDT- 2018/01/25 06:00
PHST- 2017/07/25 00:00 [received]
PHST- 2017/10/27 00:00 [accepted]
PHST- 2017/09/25 00:00 [revised]
PHST- 2018/01/25 06:00 [pubmed]
PHST- 2019/04/02 06:00 [medline]
PHST- 2018/01/25 06:00 [entrez]
PHST- 2018/07/20 00:00 [pmc-release]
AID - 10.1038/s41435-017-0009-5 [pii]
AID - 10.1038/s41435-017-0009-5 [doi]
PST - ppublish
SO  - Genes Immun. 2019 Jan;20(1):46-55. doi: 10.1038/s41435-017-0009-5. Epub 2018 Jan 
      20.