9tvz | pdb_00009tvz

FgFR4-D2 domain in complex with Fab 5936

spinqualitylabelsall models 9tvz, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9tvz is a 6 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FGFR4_HUMAN Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling. Publication Abstract from PubMed Complementarity Determining Regions (CDRs) in antibodies, and in particular the CDR-H3 loop, often display conformational plasticity that is essential for their function. Due to this flexibility, the structural investigation of antibody-antigen binding cannot exclusively rely on experimental techniques that only provide snapshots of unbound and bound states, such as X-ray crystallography. Moreover, X-ray structures can be biased due to experimental conditions and crystal packing. In this context, computational techniques, and especially conformational sampling methods, are an essential complement to experiments. This work illustrates the interest of such a coupling of methods on the structural investigation of an anti-FGFR4 (Fibroblast growth factor receptor 4) antibody. X-ray crystallography experiments revealed a very significant conformational change of the CDR-H3 loop between unbound and bound states. Structural bioinformatics methods were then applied to provide a more global picture of the conformational space of this loop, and to confirm that the observed conformations were not the result of experimental artifacts. The experimental unbound conformation was reliably predicted, and the loop conformation observed in the bound state was also predicted to be a probable conformation in the absence of the antigen. The possible existence of a third low-energy conformation, for which there is currently no experimental evidence, was substantiated by molecular simulations. We also applied recent methods based on deep learning techniques to evaluate their ability to predict conformations of the H3 loop. The results show that while these methods are very effective at predicting the structure of rigid/stable regions of proteins, they still have difficulties in accurately representing regions with more variable structure, such as this loop. Overall, this work shows that the structural study of flexible proteins remains an open field of research, and that the synergistic coupling of experimental and computational methods is essential in this context. Antibody CDR-H3 loop flexibility: Insights from X-ray crystallography, structural bioinformatics, and the limits of current deep learning methods.,Barozet A, Mathieu M, Papin D, Cameron B, Dabdoubi T, Severac A, Ferrari P, Simeon T, Bianciotto M, Cortes J J Struct Biol. 2026 Sep 12;218(4):108368. doi: 10.1016/j.jsb.2026.108368. PMID:42731718 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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