5wi9

Crystal structure of KL with an agonist FabCrystal structure of KL with an agonist Fab

Structural highlights 5wi9 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.7Å Ligands: , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KLOTB_HUMAN Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Probably inactive as a glycosidase. Increases the ability of FGFR1 and FGFR4 to bind FGF21 (By similarity). Publication Abstract from PubMed Fibroblast growth factor 21 (FGF21), an endocrine hormone in the FGF family, plays a critical role in regulating metabolic homeostasis and has emerged as a therapeutic target for metabolic diseases, including Type 2 diabetes mellitus. FGF21 functions through a receptor complex that consists of an FGF receptor (FGFR) and a co-receptor beta-Klotho. Here, we identify and biochemically and structurally characterize 39F7, a high-affinity agonistic monoclonal antibody (mAb) against beta-Klotho that mimics FGF21 function. The co-crystal structure of beta-Klotho KL1 domain in complex with 39F7 Fab revealed that the recognition of 39F7 is centered on Trp-295 of beta-Klotho in a FGF21 noncompetitive manner. KL1 adopts a (beta/alpha)8 TIM barrel fold which resembles that of beta-glycosylceramidase, but lacks molecular features for enzymatic activity, suggesting that KL1 functions as a scaffold protein instead. In vitro characterization demonstrated that, although 39F7 does not compete with FGF21, it is specific for beta-Klotho/FGFR1c activation. Furthermore, the agonistic activity of 39F7 required the full IgG molecule to be bivalent, suggesting that 39F7 functions by promoting receptor/co-receptor dimerization. Supported by negative stain EM analysis of full-length beta-Klotho, we propose a molecular model wherein the agonistic antibody 39F7 acts in a beta-Klotho- and FGFR1c-dependent manner, mimicking FGF21 activity. More importantly, 39F7 offers promising therapeutic potential in the axis of FGF21 signaling as an antibody therapy alternative to FGF21 analogs for treatment of metabolic diseases. Agonistic beta-Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions.,Min X, Weiszmann J, Johnstone S, Wang W, Yu X, Romanow W, Thibault S, Li Y, Wang Z J Biol Chem. 2018 Sep 21;293(38):14678-14688. doi: 10.1074/jbc.RA118.004343. Epub, 2018 Aug 1. PMID:30068552 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 5wi9, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image