8qfy

Crystal structure of high affinity TCR in complex with pHLA harbouring bacterial peptideCrystal structure of high affinity TCR in complex with pHLA harbouring bacterial peptide

Structural highlights

8qfy is a 10 chain structure with sequence from Homo sapiens and Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.33Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.

An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis.,Paterson RL, La Manna MP, Arena De Souza V, Walker A, Gibbs-Howe D, Kulkarni R, Fergusson JR, Mulakkal NC, Monteiro M, Bunjobpol W, Dembek M, Martin-Urdiroz M, Grant T, Barber C, Garay-Baquero DJ, Tezera LB, Lowne D, Britton-Rivet C, Pengelly R, Chepisiuk N, Singh PK, Woon AP, Powlesland AS, McCully ML, Caccamo N, Salio M, Badami GD, Dorrell L, Knox A, Robinson R, Elkington P, Dieli F, Lepore M, Leonard S, Godinho LF Proc Natl Acad Sci U S A. 2024 May 7;121(19):e2318003121. doi: , 10.1073/pnas.2318003121. Epub 2024 May 1. PMID:38691588^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Paterson RL, La Manna MP, Arena De Souza V, Walker A, Gibbs-Howe D, Kulkarni R, Fergusson JR, Mulakkal NC, Monteiro M, Bunjobpol W, Dembek M, Martin-Urdiroz M, Grant T, Barber C, Garay-Baquero DJ, Tezera LB, Lowne D, Britton-Rivet C, Pengelly R, Chepisiuk N, Singh PK, Woon AP, Powlesland AS, McCully ML, Caccamo N, Salio M, Badami GD, Dorrell L, Knox A, Robinson R, Elkington P, Dieli F, Lepore M, Leonard S, Godinho LF. An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2024 May 7;121(19):e2318003121. PMID:38691588 doi:10.1073/pnas.2318003121

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OCA

[1] Paterson RL, La Manna MP, Arena De Souza V, Walker A, Gibbs-Howe D, Kulkarni R, Fergusson JR, Mulakkal NC, Monteiro M, Bunjobpol W, Dembek M, Martin-Urdiroz M, Grant T, Barber C, Garay-Baquero DJ, Tezera LB, Lowne D, Britton-Rivet C, Pengelly R, Chepisiuk N, Singh PK, Woon AP, Powlesland AS, McCully ML, Caccamo N, Salio M, Badami GD, Dorrell L, Knox A, Robinson R, Elkington P, Dieli F, Lepore M, Leonard S, Godinho LF. An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2024 May 7;121(19):e2318003121. PMID:38691588 doi:10.1073/pnas.2318003121

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