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TitleStructural basis for hemoglobin scavenging by CD163 reveals mechanism of ligand promiscuity.
Journal, issue, pagesPLoS Biol, Vol. 24, Issue 5, Page e3003788, Year 2026
Publish dateMay 14, 2026
AuthorsRichard X Zhou / Matthew K Higgins /
PubMed AbstractThe 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 ...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.
External linksPLoS Biol / PubMed:42133656 / PubMed Central
MethodsEM (single particle)
Resolution2.79 - 3.1 Å
Structure data

EMDB-56135, PDB-9tqd:
CD163 bound to haemoglobin
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-56136: CD163 bound to haemoglobin map 1
Method: EM (single particle) / Resolution: 2.79 Å

EMDB-56137: CD163 bound to haemoglobin map 1 local refinement
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-56138: CD163 bound to haemoglobin map 2
Method: EM (single particle) / Resolution: 3.08 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CA:
Unknown entry

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-OXY:
OXYGEN MOLECULE

Source
  • homo sapiens (human)
KeywordsCELL ADHESION / CD163 / haemoglobin / haptoglobin-haemoglobin receptor

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