9x64 | pdb_00009x64
Crystal structure of DKK4 CRD1 domain
Structural highlights
FunctionDKK4_HUMAN Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease (By similarity). Publication Abstract from PubMedDickkopf (DKK) family proteins (DKK1-DKK4), which function as extracellular modulators of Wnt signaling, contain two cysteine-rich domains: CRD1 and CRD2. In DKK1, CRD1 modulates interaction with its receptor low-density lipoprotein receptor-related protein (LRP) 5/6, whereas CRD2 directly binds to LRP5/6. The crystal structure of human DKK4-CRD1 was determined at 1.83 A resolution. Crystals were obtained from refolded protein expressed as inclusion bodies and belonged to space group P2(1), with two molecules in the asymmetric unit. Initial molecular-replacement attempts using the solution NMR structure were unsuccessful, whereas an AlphaFold2-predicted model provided a clear solution. The refined structure reveals a compact fold comprising N- and C-subdomains connected by a linker region and stabilized by five conserved disulfide bonds. The crystal structure closely resembles the AlphaFold2 model, but shows larger deviations from the NMR ensemble. ANSURR analysis and hydrogen-bond comparisons indicate that the NMR models underestimate structural rigidity, particularly in beta-sheet regions, owing to fewer stabilizing hydrogen bonds. Notably, enhanced conformational variability is observed in the N-subdomain, suggesting a potential role for structural plasticity in ligand recognition. Crystal structure of human Dickkopf 4 cysteine-rich domain 1 and evaluation of conformational rigidity.,Shibata N Acta Crystallogr F Struct Biol Commun. 2026 Jul 1;82(Pt 7):245-251. doi: , 10.1107/S2053230X26006333. Epub 2026 Jun 22. PMID:42328976[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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