PMID- 37793526
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20231127
IS  - 1879-0003 (Electronic)
IS  - 0141-8130 (Linking)
VI  - 253
IP  - Pt 7
DP  - 2023 Dec 31
TI  - The rigidity of a structural bridge on HLA-I binding groove explains its 
      differential outcome in cancer immune response.
PG  - 127199
LID - S0141-8130(23)04096-5 [pii]
LID - 10.1016/j.ijbiomac.2023.127199 [doi]
AB  - The tremendous success of immune checkpoint blockade (ICB) therapy has raised the 
      great demand for the development of predictive biomarkers. A recent cancer 
      genomic study suggested that human leukocyte antigen (HLA)-B*44:02 and 
      HLA-B*15:01 alleles may act as potential biomarkers for ICB therapies, however, 
      the underlying molecular mechanisms remain largely elusive. Here, we investigated 
      the molecular origins of differential responses to ICB therapies for four 
      representative HLA alleles: HLA-B*44:02, HLA-B*15:01, HLA-B*07:02, and 
      HLA-B*53:01, using extensive all-atom molecular dynamics simulations. We first 
      demonstrated that the relatively more rigid peptide-binding groove of 
      HLA-B*15:01, than those in the other three HLA alleles, may result in challenges 
      in its recognition with T-cell receptors. Specifically, the "bridge" structure in 
      HLA-B*15:01 is stabilized through both intramolecular electrostatic interactions 
      between the HLA residues and intermolecular interactions between the HLA and the 
      antigenic peptide. These observations were further confirmed by in silico 
      mutagenesis studies, as well as simulations of several other HLA-B*15:01-peptide 
      complexes. By contrast, the "bridge" structure is either completely absent in 
      HLA-B*44:02 or easily perturbed in HLA-B*07:02 and HLA-B*53:01. Our findings 
      provide detailed structural and mechanistic insights into how HLA genotype 
      influences ICB responses and may have important implications for developing 
      immune markers.
CI  - Copyright (c) 2023 Elsevier B.V. All rights reserved.
FAU - Zhou, Hong
AU  - Zhou H
AD  - Institute of Quantitative Biology, and College of Life Sciences, Zhejiang 
      University, Hangzhou 310027, China; Shanghai Institute for Advanced Study, 
      Zhejiang University, Shanghai 201203, China.
FAU - Chan, Kevin Chun
AU  - Chan KC
AD  - Institute of Quantitative Biology, and College of Life Sciences, Zhejiang 
      University, Hangzhou 310027, China; Shanghai Institute for Advanced Study, 
      Zhejiang University, Shanghai 201203, China.
FAU - Buratto, Damiano
AU  - Buratto D
AD  - Institute of Quantitative Biology, and College of Life Sciences, Zhejiang 
      University, Hangzhou 310027, China.
FAU - Zhou, Ruhong
AU  - Zhou R
AD  - Institute of Quantitative Biology, and College of Life Sciences, Zhejiang 
      University, Hangzhou 310027, China; Shanghai Institute for Advanced Study, 
      Zhejiang University, Shanghai 201203, China; Department of Chemistry, Columbia 
      University, New York, NY 10027, United States. Electronic address: 
      rhzhou@zju.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20231002
PL  - Netherlands
TA  - Int J Biol Macromol
JT  - International journal of biological macromolecules
JID - 7909578
RN  - 0 (HLA-B Antigens)
RN  - 0 (Peptides)
RN  - 0 (Biomarkers)
SB  - IM
MH  - Humans
MH  - *HLA-B Antigens/genetics/metabolism
MH  - *Neoplasms
MH  - Peptides/chemistry
MH  - Immunity
MH  - Biomarkers
OTO - NOTNLM
OT  - Cancer immunotherapy
OT  - Free energy perturbation
OT  - HLA-I genotype
OT  - Immune response
OT  - Molecular dynamics simulations
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/10/05 01:00
MHDA- 2023/11/27 12:44
CRDT- 2023/10/04 19:13
PHST- 2023/09/07 00:00 [received]
PHST- 2023/09/28 00:00 [revised]
PHST- 2023/09/30 00:00 [accepted]
PHST- 2023/11/27 12:44 [medline]
PHST- 2023/10/05 01:00 [pubmed]
PHST- 2023/10/04 19:13 [entrez]
AID - S0141-8130(23)04096-5 [pii]
AID - 10.1016/j.ijbiomac.2023.127199 [doi]
PST - ppublish
SO  - Int J Biol Macromol. 2023 Dec 31;253(Pt 7):127199. doi: 
      10.1016/j.ijbiomac.2023.127199. Epub 2023 Oct 2.