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Human protein disulphide isomerase (hPDI) is an endoplasmic reticulum (ER) based isomerase and folding chaperone. Molecular detail of ligand recognition and specificity of hPDI are poorly understood despite the importance of the hPDI for folding secreted proteins and its implication in diseases including cancer and lateral sclerosis. We report a detailed study of specificity, interaction and dissociation constants (K d ) of the peptide-ligand Δ-somatostatin (AGSKNFFWKTFTSS) binding to hPDI using  19 F ligand-observe and  15 N, 1 H-HSQC protein-observe NMR methods. Phe residues in Δ-somatostatin are hypothesised as important for recognition by hPDI therefore, step-wise peptide Phe-to-Ala changes were progressively introduced and shown to raise the K d  from 103 + 47 μM until the point where binding was abolished when all Phe residues were modified to Ala. The largest step-changes in K d  involved the F11A peptide modification which implies the C-terminus of Δ-somatostatin is a prime recognition region. Furthermore, this study also validated the combined use of  19 F ligand-observe and complimentary  15 N, 1 H-HSQC titrations to monitor interactions from the protein’s perspective.  19 F ligand-observe NMR was ratified as mirroring  15 N protein-observe but highlighted the advantage that  19 F offers improved K d  precision due to higher spectrum resolution and greater chemical environment sensitivity.

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Combined ligand-observe 19F and protein-observe 15N,1H-HSQC NMR suggests phenylalanine as the key Δ-somatostatin residue recognized by human protein disulfide isomerase