Journal:Acta Cryst F:S2053230X24010094

Human TGFβR1 in complex with kinase inhibitor SB505124

Dr Jhon Alexander Rodriguez Buitrago ^[1]

Molecular Tour
Although it is, to an extent, held in check in the industrialized world thanks to antiviral drugs, AIDS is still endemic in many parts of the world, claiming nearly 700,000 lives annually. It is thought that anti-HIV vaccination, when available, will be more efficient against the disease in the long term, especially where regular, well-organized healthcare is lacking. However, HIV mutates rapidly, and stimulating a response that protects against all variants remains challenging. An alternative is to target a host protein, which is essential for the virus to enter cells and produce AIDS. Anti-HIV antibody RoAb13 targets a short N-terminal region of the protein CCR5, which is the main entry receptor of HIV into the human organism. Blocking that receptor would, therefore, prevent HIV infection and replication. We had earlier reported the structure of the antibody alone by X-ray crystallography (Chain et al. 2015), but the structure of the antibody complexed to the part of CCR5 to which it binds (its epitope) had remained elusive. That structure is important for designing efficient vaccines based on short synthetic immunogenic peptides that mimic the CCR5 antibody-binding region. After a long search for co-crystallization conditions involving both the whole N-terminal region of CCR5 and the minimally required binding region to its antibody (the ‘core peptide’), and the analysis and comparison of X-ray crystallographic electron density maps obtained from several crystals, we have finally located the core peptide of the CCR5 receptor bound to RoAb13. It binds at the hypervariable region ‘CDR3’ of the antibody’s light chain, an expected antigen-binding site. Even though the best attainable resolution is not particularly high at 3 Å, we have been able to identify the interacting residues between antibody and peptide. Furthermore, the core peptide was found to bind to accommodate the full length of the CCR5 N-terminus. The structural insights thus may inform the design of better peptide analogs for use as immunogens in vivo. These analogs may ultimately provide the basis for active immunization vaccines to stimulate an antibody response to native CCR5, which will thwart HIV infection.

References

1. ↑ Rodriguez Buitrago JA, Landström M, Wolf-Watz M. Human transforming growth factor β type I receptor in complex with kinase inhibitor SB505124. Acta Crystallogr F Struct Biol Commun. 2024 Nov 1. PMID:39441620 doi:10.1107/S2053230X24010094