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Updated: May 16, 2026

Avidity-based Extracellular Interaction Screening (AVEXIS) for the Scalable Detection of Low-affinity Extracellular Receptor-Ligand Interactions
12:30

Avidity-based Extracellular Interaction Screening (AVEXIS) for the Scalable Detection of Low-affinity Extracellular Receptor-Ligand Interactions

Published on: March 5, 2012

Structural basis for hemoglobin scavenging by CD163 reveals mechanism of ligand promiscuity

Richard X Zhou1,2, Matthew K Higgins1,2

  • 1Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

Plos Biology
|May 14, 2026
PubMed

The scavenger receptor CD163 detoxifies free hemoglobin released on erythrocyte lysis to prevent oxidative damage. The best understood route for hemoglobin detoxification involves the formation of haptoglobin-hemoglobin complexes that bind CD163 and are internalized into macrophages, resulting in hemoglobin degradation. However, during conditions such as sickle cell anemia or malaria, haptoglobin is depleted. CD163 can then act as a lower-affinity receptor for free hemoglobin. Previous studies revealed that CD163 forms a multimeric "base," which presents "arms" that form a binding site for haptoglobin-hemoglobin. In this study, we use cryogenic electron microscopy to reveal how human CD163 binds hemoglobin tetramers in a process that, unlike haptoglobin-hemoglobin uptake, requires a full trimeric CD163 assembly to achieve sufficient binding. We reveal how flexibility at the calcium-mediated base, combined with a hinge between receptor domains 2 and 3, allows the arms to wrap around diverse ligands. This brings together multiple small binding surfaces from different domains to form cradles for different ligands. These adaptations allow the scavenger receptor to be promiscuous, protecting us from oxidative damage caused by hemoglobin release in various pathological conditions.

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