9nwu | pdb_00009nwu

Crystal structure of a high affinity VL-VH tetrabody for the erythropoietin receptor

spinqualitylabelsall models 9nwu, resolution 1.96Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9nwu is a 4 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 1.96Å Ligands: CL, NA, NHE, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Erythropoietin (EPO) initiates EPO receptor (EPOR) signaling in hematopoietic cells by binding to an asymmetric EPOR dimer through two different sites. We engineered dimeric diabody-Fc (Db-Fc) fusion proteins that appeared to act as potent agonists of human EPOR in cell proliferation assays. However, detailed analysis of their oligomeric forms revealed that the predominant Db-Fc species bound EPOR with high affinity but failed to induce cell proliferation. Instead, a minor oligomeric form, identified as a putative tetrabody (Tb) fused to two Fc domains (Tb-Fc(2)), proved to be the minimal active form. The existence of a tetrameric agonist was further supported by crystallography, which revealed an asymmetric Tb structure. Additionally, the structure of an antigen-binding fragment (Fab) bound to EPOR revealed an epitope distinct from the EPO binding sites, and structural modeling showed that engagement of two of the four binding sites on the Tb could form an asymmetric EPOR dimer nearly identical to the active conformation recruited by EPO. In a knock-in mouse model, where mouse EPOR was replaced by human EPOR, purified Tb-Fc(2) stimulated erythropoiesis with greater potency, efficacy, and duration than darbepoetin, a recombinant EPO that is the leading therapeutic erythropoiesis-stimulating agent (ESA). Collectively, these findings demonstrate that asymmetric tetravalent antibodies such as Tb-Fc(2) represent promising next-generation ESAs that provide enhanced potency, efficacy, and durability. Moreover, they may reduce the oncogenic and cardiovascular risks associated with the pleiotropy of EPO. An asymmetric tetrabody is a potent and efficacious agonist of the erythropoietin receptor in vitro and in vivo.,Adams JJ, Blazer LL, Chung J, Karimi M, Davidson T, Bruce HA, Singer AU, Yang N, Cardarelli L, Pot I, Colombo L, Huang LJ, Ma Y, Michnick SW, Moe OW, Sidhu SS Protein Sci. 2025 Oct;34(10):e70292. doi: 10.1002/pro.70292. PMID:40960423 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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