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TitleThe resting and ligand-bound states of the membrane-embedded human T-cell receptor-CD3 complex.
Journal, issue, pagesbioRxiv, Year 2024
Publish dateSep 20, 2024
AuthorsRyan Q Notti / Fei Yi / Søren Heissel / Martin W Bush / Zaki Molvi / Pujita Das / Henrik Molina / Christopher A Klebanoff / Thomas Walz
PubMed AbstractThe T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain( ). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte ...The T-cell receptor (TCR) initiates T-lymphocyte activation, but mechanistic questions remain( ). Here, we present cryogenic electron microscopy structures for the unliganded and human leukocyte antigen (HLA)-bound human TCR-CD3 complex in nanodiscs that provide a native-like lipid environment. Distinct from the "open and extended" conformation seen in detergent( ), the unliganded TCR-CD3 in nanodiscs adopts two related "closed and compacted" conformations that represent its physiologic resting state . By contrast, the HLA-bound complex adopts the open and extended conformation, and conformation-locking disulfide mutants show that ectodomain opening is necessary for maximal ligand-dependent T-cell activation. Together, these results reveal allosteric conformational change during TCR activation and highlight the importance of native-like lipid environments for membrane protein structure determination.
External linksbioRxiv / PubMed:37662363 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.5 Å
Structure data

41658

8tw4

EMDB-41658, PDB-8tw4:
TCR in nanodisc ND-I
Method: EM (single particle) / Resolution: 3.3 Å

41660

8tw6

EMDB-41660, PDB-8tw6:
TCR in nanodisc ND-II
Method: EM (single particle) / Resolution: 3.1 Å

44417

9bbc

EMDB-44417, PDB-9bbc:
TCR GDN detergent micelle
Method: EM (single particle) / Resolution: 3.3 Å

45166

9c3e

EMDB-45166, PDB-9c3e:
TCR - CD3 complex bound to HLA
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CLR:
CHOLESTEROL

Source
  • homo sapiens (human)
  • escherichia coli str. k-12 substr. mg1655 (bacteria)
  • human respiratory syncytial virus
KeywordsIMMUNE SYSTEM / T-cell receptor / TCR / 1G4 / nanodisc / CD3 / HLA / NY-ESO-1

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