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Instruments / Technical Area	Publication Details	Published
B21-High Throughput SAXS I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes Lucy C. Walters , Daniel Rozbesky , Karl Harlos , Max Quastel , Hong Sun , Sebastian Springer , Robert P. Rambo , Fiyaz Mohammed , E. Yvonne Jones , Andrew J. Mcmichael , Geraldine M. Gillespie Cell Reports 39 DOI: 10.1016/j.celrep.2022.110959 Diamond Proposal Number(s): [19946] Open Access Show Abstract ▼ Abstract: MHC-E regulates NK cells by displaying MHC class Ia signal peptides (VL9) to NKG2A:CD94 receptors. MHC-E can also present sequence-diverse, lower-affinity, pathogen-derived peptides to T cell receptors (TCRs) on CD8+ T cells. To understand these affinity differences, human MHC-E (HLA-E)-VL9 versus pathogen-derived peptide structures are compared. Small-angle X-ray scatter (SAXS) measures biophysical parameters in solution, allowing comparison with crystal structures. For HLA-E-VL9, there is concordance between SAXS and crystal parameters. In contrast, HLA-E-bound pathogen-derived peptides produce larger SAXS dimensions that reduce to their crystallographic dimensions only when excess peptide is supplied. Further crystallographic analysis demonstrates three amino acids, exclusive to MHC-E, that not only position VL9 close to the α2 helix, but also allow non-VL9 peptide binding with re-configuration of a key TCR-interacting α2 region. Thus, non-VL9-bound peptides introduce an alternative peptide-binding motif and surface recognition landscape, providing a likely basis for VL9- and non-VL9-HLA-E immune discrimination.	Jun 2022
I02-Macromolecular Crystallography	The C-terminal tail of the bacterial translocation ATPase SecA modulates its activity Mohammed Jamshad , Timothy J. Knowles , Scott A. White , Douglas G Ward , Fiyaz Mohammed , Kazi Fahmida Rahman , Max Wynne , Gareth W. Hughes , Günter Kramer , Bernd Bukau , Damon Huber Elife 8 DOI: 10.7554/eLife.48385 Diamond Proposal Number(s): [10369] Open Access Show Abstract ▼ Abstract: In bacteria, the translocation of proteins across the cytoplasmic membrane by the Sec machinery requires the ATPase SecA. SecA binds ribosomes and recognises nascent substrate proteins, but the molecular mechanism of nascent substrate recognition is unknown. We investigated the role of the C-terminal tail (CTT) of SecA in nascent polypeptide recognition. The CTT consists of a flexible linker (FLD) and a small metal-binding domain (MBD). Phylogenetic analysis and ribosome binding experiments indicated that the MBD interacts with 70S ribosomes. Disruption of the MBD only or the entire CTT had opposing effects on ribosome binding, substrate-protein binding, ATPase activity and in vivo function, suggesting that the CTT influences the conformation of SecA. Site-specific crosslinking indicated that F399 in SecA contacts ribosomal protein uL29, and binding to nascent chains disrupts this interaction. Structural studies provided insight into the CTT-mediated conformational changes in SecA. Our results suggest a mechanism for nascent substrate protein recognition.	Jun 2019
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	BTN3A1 discriminates γδ T cell phosphoantigens from non-antigenic small molecules via a conformational sensor in its B30.2 domain Mahboob Salim , Timothy J. Knowles , Alfie T. Baker , Martin S. Davey , Mark Jeeves , Pooja Sridhar , John Wilkie , Carrie R. Willcox , Hachemi Kadri , Taher E. Taher , Pierre Vantourout , Adrian Hayday , Youcef Mehellou , Fiyaz Mohammed , Benjamin E. Willcox Acs Chemical Biology DOI: 10.1021/acschembio.7b00694 Diamond Proposal Number(s): [14692] Show Abstract ▼ Abstract: Human Vγ9/Vδ2 T-cells detect tumour cells and microbial infections by recognising small phosphorylated prenyl metabolites termed phosphoantigens (P-Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vγ9/Vδ2 T-cells, however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag are discriminated from non-antigenic small molecules. Here, we utilised NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1. Whereas the BTN3A1 Immunoglobulin Variable domain failed to bind P-Ag, the intracellular B30.2 domain bound a range of negatively-charged small molecules, including P-Ag, in a positively-charged surface pocket. However, NMR chemical shift perturbations indicated BTN3A1 discriminated P-Ag from non-antigenic small molecules by their ability to induce a specific conformational change in the B30.2 domain that propagated from the P-Ag binding site to distal parts of the domain. These results suggest BTN3A1 selectively detects P-Ag intracellularly via a conformational antigenic sensor in its B30.2 domain, and have implications for rational design of antigens for Vγ9/Vδ2 -based T-cell immunotherapies.	Sep 2017

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