The hinge region links the antigen binding Fab part to the constant Fc domain in immunoglobulins. For the hinge peptide derivative [AcThr(OtBu)-Cys-Pro-Pro-Cys-Pro-Ala-ProNH2]2 the assignment of the 1H and 13C resonances was achieved by two-dimensional nmr techniques: total correlation spectroscopy (TOCSY), nuclear Overhauser enhancement spectroscopy (NOESY), rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), heteronuclear multiple quantum coherence (HMQC) transfer, and a HSQC (modified Overbodenhausen experiment) with high resolution in F1, which was several times folded in F1 but still phase correctable. Conformational relevant parameters (78 nuclear Overhauser effect distance restraints, 3JHH for prochiral assignments, temperature gradients) were determined by nmr and served as input data for molecular dynamics (MD) structure refinement. A simulated model compound corresponding to the [Cys-Pro-Pro-Cys]2 core elongated by the peptide chains in the Fab and Fc direction served as a starting structure for the final MD run. The conformation calculated in in vacuo does not agree with the C2 symmetry required from nmr data, but the structure obtained by a water simulation fulfills the requirement. Here the core of the hinge peptide derivative adopts a polyproline II double helix as in the x-ray structure of IgG1. Hence, segments responsible for the internal flexibility are located outside the core as confirmed by the flexibility of the solvent exposed C termini.
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http://dx.doi.org/10.1002/bip.360311007 | DOI Listing |
J Med Chem
January 2025
Immunology Research Unit GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
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School of Medicine, Southeast University, Nanjing, Jiangsu, China.
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View Article and Find Full Text PDFJ Am Chem Soc
January 2025
Laboratoire de Chimie Supramoléculaire, Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Université de Strasbourg, Strasbourg 67000, France.
SAr reactions were remarkably accelerated using a pretargeting and activating unit based on dynamic covalent chemistry (DCvC). A Cys attack at the C-F bond on the aromatic ring of salicylaldehyde derivatives was only observed upon iminium formation with a neighboring Lys residue of model small peptides. Such self-activation was ascribed to the stronger electron-withdrawing capability of the iminium bond with respect to that of the parent aldehyde that stabilized the transition state of the reaction, together with the higher preorganization of the reactive groups in the cationic aldiminium species.
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November 2024
School of Pharmacy, Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai 201203, China.
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