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- PDB-9fnm: Structure of human haptoglobin -

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Basic information

Entry
Database: PDB / ID: 9fnm
TitleStructure of human haptoglobin
Components
  • Haptoglobin beta chain
  • Isoform 2 of Haptoglobin alpha chain
KeywordsPROTEIN BINDING / acute phase / hemolysis / hemoglobin binding / reactive oxygen specis
Function / homology
Function and homology information


negative regulation of hydrogen peroxide catabolic process / negative regulation of oxidoreductase activity / zymogen activation / hemoglobin binding / haptoglobin-hemoglobin complex / antioxidant activity / immune system process / Scavenging of heme from plasma / endocytic vesicle lumen / acute-phase response ...negative regulation of hydrogen peroxide catabolic process / negative regulation of oxidoreductase activity / zymogen activation / hemoglobin binding / haptoglobin-hemoglobin complex / antioxidant activity / immune system process / Scavenging of heme from plasma / endocytic vesicle lumen / acute-phase response / defense response / response to hydrogen peroxide / specific granule lumen / tertiary granule lumen / blood microparticle / defense response to bacterium / serine-type endopeptidase activity / Neutrophil degranulation / extracellular space / extracellular exosome / extracellular region
Similarity search - Function
Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.52 Å
AuthorsTorvund-Jensen, M. / Andersen, C.B.F.
Funding support Denmark, 1items
OrganizationGrant numberCountry
Danish Council for Independent Research11-107169 Denmark
CitationJournal: Nat Commun / Year: 2024
Title: The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging.
Authors: Anders Etzerodt / Jakob Hauge Mikkelsen / Morten Torvund-Jensen / Dorle Hennig / Thomas Boesen / Jonas Heilskov Graversen / Søren Kragh Moestrup / Justin M Kollman / Christian Brix Folsted Andersen /
Abstract: CD163, a macrophage-specific receptor, plays a critical role in scavenging hemoglobin released during hemolysis, protecting against oxidative effects of heme iron. In the bloodstream, hemoglobin is ...CD163, a macrophage-specific receptor, plays a critical role in scavenging hemoglobin released during hemolysis, protecting against oxidative effects of heme iron. In the bloodstream, hemoglobin is bound by haptoglobin, leading to its immediate endocytosis by CD163. While haptoglobin's structure and function are well understood, CD163's structure and its interaction with the haptoglobin-hemoglobin complex have remained elusive. Here, we present the cryo-electron microscopy structure of the entire extracellular domain of human CD163 in complex with haptoglobin-hemoglobin. The structure reveals that CD163 assembles into trimers (and to some extent dimers), binding haptoglobin-hemoglobin in their center. Key acidic residues in CD163 interact with lysine residues from both haptoglobin and hemoglobin. Calcium-binding sites located near the haptoglobin-hemoglobin interface in CD163 provide explanation for the calcium dependence of the interaction. Furthermore, we show that the interaction facilitating CD163 oligomerization mimics ligand binding and is also calcium dependent. This structural insight into CD163 advances our understanding of its role in hemoglobin scavenging as well as its broader relevance to structurally related scavenger receptors.
History
DepositionJun 10, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2 of Haptoglobin alpha chain
B: Haptoglobin beta chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7233
Polymers36,5022
Non-polymers2211
Water1,67593
1
A: Isoform 2 of Haptoglobin alpha chain
B: Haptoglobin beta chain
hetero molecules

A: Isoform 2 of Haptoglobin alpha chain
B: Haptoglobin beta chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,4476
Polymers73,0054
Non-polymers4422
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x,y,-z-11
Buried area6900 Å2
ΔGint-41 kcal/mol
Surface area30350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.887, 77.639, 65.085
Angle α, β, γ (deg.)90.000, 92.508, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Components on special symmetry positions
IDModelComponents
11B-1105-

HOH

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Components

#1: Protein Isoform 2 of Haptoglobin alpha chain / Zonulin / Isoform 2 of Haptoglobin alpha chain


Mass: 9204.204 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00738
#2: Protein Haptoglobin beta chain


Mass: 27298.049 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00738
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 93 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.27 Å3/Da / Density % sol: 62.41 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 4.5
Details: 6% 2-propanol 0.1 M sodium acetate trihydrate 26% PEG MME 550

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-2 / Wavelength: 1.03841 Å
DetectorType: MAR CCD 300 mm / Detector: CCD / Date: Nov 26, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03841 Å / Relative weight: 1
ReflectionResolution: 2.516→65.023 Å / Num. obs: 14717 / % possible obs: 95.6 % / Redundancy: 4.18 % / CC1/2: 0.998 / Rmerge(I) obs: 0.047 / Net I/σ(I): 20.23
Reflection shellResolution: 2.516→2.6 Å / Rmerge(I) obs: 0.218 / Mean I/σ(I) obs: 5.45 / Num. unique obs: 1148 / CC1/2: 0.971

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.52→28.11 Å / SU ML: 0.3052 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.2342
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2272 1478 10.04 %
Rwork0.1912 13239 -
obs0.1948 14717 96.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.88 Å2
Refinement stepCycle: LAST / Resolution: 2.52→28.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2451 0 14 93 2558
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00252526
X-RAY DIFFRACTIONf_angle_d0.58523432
X-RAY DIFFRACTIONf_chiral_restr0.0434380
X-RAY DIFFRACTIONf_plane_restr0.0045438
X-RAY DIFFRACTIONf_dihedral_angle_d14.0066939
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.52-2.60.27671080.2508884X-RAY DIFFRACTION70.96
2.6-2.690.28391270.24911240X-RAY DIFFRACTION99.64
2.69-2.80.29431400.24591234X-RAY DIFFRACTION99.71
2.8-2.920.30011400.25361217X-RAY DIFFRACTION99.34
2.92-3.080.33671440.22991248X-RAY DIFFRACTION99.57
3.08-3.270.25091390.22261231X-RAY DIFFRACTION99.42
3.27-3.520.25351300.21561252X-RAY DIFFRACTION99.5
3.52-3.880.21851380.17481247X-RAY DIFFRACTION99.57
3.88-4.440.16891380.1541228X-RAY DIFFRACTION99.27
4.44-5.580.18461380.14781262X-RAY DIFFRACTION99.36
5.58-28.110.19851360.18241196X-RAY DIFFRACTION93.08
Refinement TLS params.Method: refined / Origin x: 21.4723554785 Å / Origin y: 50.4807119306 Å / Origin z: 0.90680621576 Å
111213212223313233
T0.273497619191 Å2-0.0137936520259 Å20.0399174065174 Å2-0.259401171253 Å20.0147534635736 Å2--0.323300856534 Å2
L0.972598333 °2-0.0335620367185 °20.708875347465 °2-1.0769280338 °20.194368147243 °2--2.43492318687 °2
S0.0182002403078 Å °-0.0541142706242 Å °-0.0841360563605 Å °0.177293433234 Å °0.0887750811503 Å °-0.161952277525 Å °0.0184715155755 Å °0.0269495008801 Å °-0.112132651495 Å °
Refinement TLS groupSelection details: all

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