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Crystal strucrue of HuHF-C2-ALY complex
Structural highlights
FunctionFRIH_HUMAN Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Has ferroxidase activity. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney (By similarity). Publication Abstract from PubMedAlthough ferritin, as a versatile nanocarrier, has been engineered to improve cargo loading efficiency for various functions, including therapeutic applications, a universal design strategy enabling tunable molecular binding remains an unmet challenge. This study reports an AI-aided structure-guided engineering approach targeting the ferroxidase center of recombinant human heavy-chain ferritin (rHuHF), aiming to achieve either universal molecular binding or high-affinity specific recognition. Through site-directed mutagenesis of key residues within and flanking the ferroxidase center, two rHuHF variants (rHuHF-C1 and rHuHF-C2) were generated. X-ray crystallographic analysis revealed that the engineered pocket within rHuHF-C2 can accommodate a broad range of hydrophobic molecules (e.g., Curcumin, CUR) via hydrophobic interactions, thus validating their universal molecular binding capability. On the other hand, leveraging AI-assisted rational design, a variant (rHuHF-71) was subsequently engineered to specifically bind CUR with enhanced affinity, facilitated by the formation of hydrogen bonds and optimized hydrophobic contacts. This work establishes a generalizable strategy, designated as "Excavation, Rebuilding, and Validation", for engineering ferritin nanocages with tunable binding specificities, which holds great promise for advancing the development of protein-based drug delivery systems and the design of small-molecule binding proteins. Redesign of the Ferritin Ferroxidase Center for Universal Molecular Binding or Specific Recognition.,Wang W, Yao H, Gong W, Ma D, Qiao J, Zhang Y, Wu L, Fan C, Zhao Y, Wang Z, Jia Z, Guo Y, Zhang N, Zhao G, Yun Y, Wang H Small. 2026 May 24:e73922. doi: 10.1002/smll.73922. PMID:42178779[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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