Conformational dynamics in interleukin 17A and 17F functional complexes is a key determinant of receptor A affinity and specificity

Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein–Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases

“…Waters et al have reported, based on protein NMR data, that a number of regions of the IL-17A dimer interconvert between at least two conformations, and it is possible that compound binding shifts the equilibrium and essentially locks IL-17A in a conformation that cannot bind well to IL-17RA. This also fits with the structural information of the IL-17A/IL-17RA complex, where a contraction of the central pocket is observed, causing the C α –C α distance between the Leu120 residues in chains A and B to shrink to 5.7 Å.…”

IL-17-induced dimerization of IL-17RA drives the formation of the IL-17 signalosome to potentiate signaling

“…The picture that is emerging from this work, however, is a mechanism whereby IL-17RA receptor sharing by IL-17 family members is not only governed by the intrinsic flexibility of these cytokines ( Waters et al, 2021 ) but also by order/disorder transitions of ligand-binding loops within the D1 domain of the receptor and by the fine adjustment of the position of its D2 domain. Starting from the resting state of the IL-17RA receptor, the rotation of the D2 domain and the subsequent receptor homodimerization induced by IL-17 binding are a likely prelude to the assembly of the membrane-proximal signaling machinery.…”

Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism

“…Unlabelled and uniformly 15 N, 15 N/ 13 C, 15 N/ 2 H and 15 N/ 13 C/ 2 H labelled samples of mature human IL-17AA and IL-17FF homodimers (residues 24-155 and 31-163 respectively) and IL-17AF hetero-dimers were prepared as described previously. 21…”

“…Spectra assignments for the apo-IL-17 homo-and hetero-dimers have been reported previously. 21 15 N relaxation data were acquired on a Bruker AV III HD 600 MHz spectrometer using in-house written, standard trosy based T 1 , T 2 and NOE experiments. 25,26 All NMR data were processed using NMRPipe 27 with linear prediction used to extend the effective acquisition times by up to 2-fold in nitrogen in regular sampled data.…”