CODSWALLOP

Hemoglobin subunit alpha

Homo sapiens · seed 4HHB_1 · 141 aa · family defined as ≥30% identity to that seed · compiled 07 October 2026

CATH and SCOP identifiers come from the RCSB's own structure annotations, which the Domains panel already reads, so these are looked up rather than guessed at.

533Entries 1,036Entities 245Constructs 60Organisms 1,034Ligand-bound
0.91 ÅBest res.
2.07 ÅMedian res.

Every figure here is counted over the whole family rather than quoted from one entry.

The reference structure

4MQI, the structure every other member of this family is superposed onto. Rendered by the RCSB and embedded here: the live app shows an interactive viewport, which a document that fetches nothing cannot.

Rendered structure of 4MQI
4MQI at the RCSB · open it in the 3D viewer

Which residues anyone has ever seen

How many of this family's constructs contain each residue of the seed. A trough is a stretch nobody has put in a construct, which is a construct-design answer rather than a disorder one.

1701411036 constructs

Constructs, most-used first

245 distinct constructs across 533 entries. 734 polymer entities differ from the UniProt canonical sequence in some way, 0 carry a recognised expression tag and 0 carry a fusion partner.

"Differs from canonical" is not the same as "engineered". The canonical sequence is the full gene product, so a secreted protein whose structures all start after its signal peptide counts every one of them as different: lysozyme's most-used construct, residues 19–147 on 1,239 entities, is simply the mature protein. Read the construct column below for what was actually done, rather than this count.

EntitiesLengthBest (Å)Best entryWhat was made
248 141 1.25 1IRD residues 2-142
196 146 1.25 1IRD residues 2-147
30 142 1.59 1BZ1 matches the canonical sequence
27 147 1.70 1DXT matches the canonical sequence
20 146 1.45 2D5X matches the canonical sequence
17 145 1.85 5E29 residues 3-147
15 145 1.34 6II1 matches the canonical sequence
12 141 1.60 1NS9 residues 2-142; N83D, D86N
12 143 1.30 2H8F matches the canonical sequence
12 146 1.30 2H8F residues 2-147
11 140 1.92 4MQI residues 2-141
11 141 1.75 2QSS residues 2-142
11 146 1.40 6KAO residues 2-147; E7K
10 139 2.20 6HAL residues 3-141
9 146 1.70 1DXU residues 2-147; V2M
9 146 1.76 5E6E residues 2-147; E7V
6 140 3.10 9S3P residues 3-142
6 143 1.80 2AA1 matches the canonical sequence
6 146 0.91 3QM5 matches the canonical sequence
6 146 1.25 3D1K matches the canonical sequence
6 146 1.39 6ZMX matches the canonical sequence
5 142 2.20 8WIZ matches the canonical sequence
5 146 1.80 1C7C residues 2-147; V2M, N109K
5 146 2.20 8WIZ matches the canonical sequence
4 141 1.07 2W72 residues 2-142; V2M, L30Y, H59Q

Showing the 25 most-used of 245.

Positions people deliberately mutate

Columns where the wild-type residue still dominates but a real minority carries something else, which is a different question from "what varies across species".

M76L 65% V73L 65% N78G 63% N68D 62% S131G 62% G57A 61% A115K 61% S35V 61% L34V 60% A63L 60% A13L 60% T8S 59% T67S 59% T38W 59% H89D 58% D64G 58% A82T 58% A120P 58% G22D 58% F36Y 58% P77K 58% L113F 57% D85E 57% V1H 57% A111H 57% T108V 57% T134N 57% S133A 56% Y24V 56% E30G 56%

What it assembles into

Oligomeric stateChainsEntriesShare
tetrameric4 465 87.2%
trimeric3 15 2.8%
dimeric2 14 2.6%
monomeric1 12 2.3%
hexameric6 12 2.3%
pentameric5 5 0.9%
heptameric7 5 0.9%
decameric10 3 0.6%

387 entries have the depositor's assembly corroborated by PISA, 142 carry the depositor's word alone and 4 were assigned by PISA where the depositor gave none. The middle figure is not a disagreement: PISA may have returned nothing or never run. 14 entries carry more than one assembly with different chain counts, so they have no single answer to quote: 1QXD, 1QXE, 1SDK, 1SDL, 1UC3, 1Z8U, 2ZLT, 2ZLV, 3A59, 3CY5, 3DHR, 3GYS, 8DOV, 9JYU.

Domain architecture

Every source's own domains on the seed axis, one row each. They are not merged: Pfam, CATH, SCOP and InterPro disagree about boundaries, and a merged track would state a consensus none of them gave.

CATHGlobinsSCOP2BGlobin-likeGlobin-likeGlobin-likeGlobin-likeGlobin-likeGlobin-likeGlobin-likeGlobin-like170141
DomainSourceSpan (seed)Chains
GlobinsCATH 1.10.490.10 2–141 870
Globin-likeSCOP2B 8039586 1–141 20
Globin-likeSCOP2B 8036374 1–141 13
Globin-likeSCOP2B 8036375 1–141 13
Globin-likeSCOP2B 8039836 2–141 356
Globin-likeSCOP2B 8039587 2–141 20
Globin-likeSCOP2B 8039838 3–141 340
Globin-likeSCOP2B 8042195 3–141 11
Globin-likeSCOP2B 8042196 23–141 11

What binds it

HEM HEM526 entries HNI HNI18 entries NAG NAG13 entries 2FU 2FU12 entries MBN MBN12 entries ACE ACE5 entries O4B O4B5 entries DG2 DG24 entries PEM PEM3 entries IHP IHP3 entries L35 L353 entries RQ3 RQ32 entries
ComponentClassNameEntriesBest (Å)
HEMcofactor Protoporphyrin Ix Containing Fe 526 0.91
CMOsolvent Carbon Monoxide 129 0.96
OXYsolvent Oxygen Molecule 73 0.91
SO4ion Sulfate Ion 39 0.95
PO4ion Phosphate Ion 23 1.07
GOLcryoprotectant Glycerol 22 1.09
HNIligand Protoporphyrin Ix Containing Ni(Ii) 18 1.40
NAGcofactor 2-Acetamido-2-Deoxy-Beta-D-Glucopyranose 13 2.80
2FUligand But-2-Enedial 12 1.40
MBNligand Toluene 12 1.25
CAion Calcium Ion 12 2.64
EDOcryoprotectant 1,2-Ethanediol 10 0.91
CYNion Cyanide Ion 9 0.91
NOsolvent Nitric Oxide 8 0.95
ACEligand Acetyl Group 5 1.25
NO2ion Nitrite Ion 5 1.80
O4Bligand 1,4,7,10,13,16-Hexaoxacyclooctadecane 5 1.48
DG2ligand (2r)-2,3-Diphosphoglyceric Acid 4 1.80
NAion Sodium Ion 3 1.39
CLion Chloride Ion 3 2.10

How it crystallises

Parsed from the free text 382 depositors typed into _exptl_crystal_grow.pdbx_details, out of 424 entries that recorded anything at all. Median pH 7.0 (range 4.0 to 9.5).

Precipitants

PEG × Ammonium sulfate × Ammonium phosphate × Sodium chloride × Sodium citrate × Lithium sulfate × PEG (unspecified) × Magnesium chloride × Isopropanol × MPD × Jeffamine × Sodium formate × Calcium chloride × Sodium malonate ×

Buffers

Phosphate × Citrate × HEPES × Tris × Sodium cacodylate × Sodium acetate × MES × Bis-Tris × Bis-Tris propane × ADA × Glycine × Imidazole ×

Which entries to trust

530 entries carry a wwPDB validation report: 231 clean, 159 worth a check and 140 with something to explain. Median clashscore 7.2, median RSRZ outliers 1.57%, median R-free minus R-work 0.046. 455 have released structure factors.

Across species

OrganismEntriesBest (Å)Ligand-boundSeed covered
Homo sapiens365 1.07 719 100%
Equus caballus21 1.45 42 100%
Bos taurus16 1.34 28 100%
Trematomus bernacchii12 1.30 24 99%
Trematomus newnesi7 1.25 14 99%
Meleagris gallopavo6 1.39 12 100%
Alligator mississippiensis5 2.20 10 100%
Thunnus atlanticus9 0.91 9 72%
Oncorhynchus mykiss4 1.35 8 99%
Perca flavescens4 1.90 8 99%
Felis catus4 2.00 8 100%
Columba livia3 1.44 6 100%

Seed sequence

141 residues, numbered every ten. Every identity figure in this document is measured against this sequence.

active or binding site modified residue or glycosylation disulphide cysteine transmembrane or signal the 15 most-substituted positions

1VLSPADKTNV KAAWGKVGAH AGEYGAEALE RMFLSFPTTK TYFPHFDLSH GSAQVKGHGK
61KVADALTNAV AHVDDMPNAL SALSDLHAHK LRVDPVNFKL LSHCLLVTLA AHLPAEFTPA
121VHASLDKFLA SVSTVLTSKY R

Sites are UniProt's curated features where the seed is a UniProt accession; the substituted positions are measured from this family's own alignment rather than annotated, and only the fifteen most substituted are marked: every position carrying a minority substitution would be most of the protein, because the family holds orthologues. A residue can carry more than one and is drawn with the first that applies, in the order of the key above.

Primary citations

One record per paper, not per entry.

YearCitation
2026 Oxidative Characteristics of Turkey Hemoglobin A Containing Covalently Bound Epigallocatechin Gallate. J.Agric.Food Chem. doi:10.1021/acs.jafc.5c17482
2026 Recombinant Hemoglobin rHb0.1 with Cross-Linked Alpha Subunits Preferentially Crystallizes in the beta 4 Oligomeric State, Potentially Driven by a beta G18(H116I) Mutation. Acs Omega doi:10.1021/acsomega.5c11376
2026 Structural basis for hemoglobin scavenging by CD163 reveals mechanism of ligand promiscuity. Plos Biol. doi:10.1371/journal.pbio.3003788
2026 Refining the mechanism of heme acquisition from free hemoglobin by Staphylococcus aureus IsdH. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.2601134123
2026 Hemoglobin's alpha-Helix-to-beta-Sheet Transition Enables Targeted mRNA Delivery to the Lung. Adv Sci doi:10.1002/advs.76092
2026 Structural Basis of Hemoglobin Amyloid Fibrils Revealed by cryo-EM and Molecular Dynamics Simulations. Nano Lett. doi:10.1021/acs.nanolett.6c02217
2025 Molecular basis of hemoglobin binding and heme removal in Corynebacterium diphtheriae. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.2411833122
2025 Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease. Nat Commun doi:10.1038/s41467-025-56578-3
2025 Conformational analysis of liganded human hemoglobin by cryo electron microscopy Biorxiv doi:10.1101/2025.07.07.661630
2025 Preparation of oxygen-sensitive proteins for high-resolution cryoEM structure determination using blot-free vitrification. Nat Commun doi:10.1038/s41467-025-58243-1
2025 Scavenger receptor CD163 multimerises to allow uptake of diverse ligands. Nat Commun doi:10.1038/s41467-025-62054-9
2025 Calcium-dependent oligomerization of scavenger receptor CD163 facilitates the endocytosis of ligands. Nat Commun doi:10.1038/s41467-025-62013-4
2025 Hemoglobin receptor redundancy in Staphylococcus aureus : molecular flexibility as a determinant of divergent hemophore activity. J Struct Biol X doi:10.1016/j.yjsbx.2025.100138
2025 Structural elucidation of the haptoglobin-hemoglobin clearance mechanism by macrophage scavenger receptor CD163. Plos Biol. doi:10.1371/journal.pbio.3003264
2024 Improving Protein Expression, Stability, and Function with ProteinMPNN. J.Am.Chem.Soc. doi:10.1021/jacs.3c10941
2024 The structure of a haemoglobin-nanobody complex reveals human beta-subunit-specific interactions. Febs Lett. doi:10.1002/1873-3468.14958
2024 The unique allosteric property of crocodilian haemoglobin elucidated by cryo-EM. Nat Commun doi:10.1038/s41467-024-49947-x
2024 The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging. Nat Commun doi:10.1038/s41467-024-55171-4
2023 Structural and oxidative investigation of a recombinant high-yielding fetal hemoglobin mutant. Front Mol Biosci doi:10.3389/fmolb.2023.1133985
2023 Crystal structural investigations of heme protein derivatives resulting from reactions of aryl- and alkylhydroxylamines with human hemoglobin. J.Inorg.Biochem. doi:10.1016/j.jinorgbio.2023.112304
2023 Anaerobic fixed-target serial crystallography using sandwiched silicon nitride membranes. Acta Crystallogr D Struct Biol doi:10.1107/S205979832300880X
2023 Protein-to-structure pipeline for ambient-temperature crystallography at VMXi Iucrj doi:10.1107/S2052252523003810
2023 GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model. Br.J.Haematol. doi:10.1111/bjh.18771
2023 The Shr receptor from Streptococcus pyogenes uses a cap and release mechanism to acquire heme-iron from human hemoglobin. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.2211939120
2023 Uniform thin ice on ultraflat graphene for high-resolution cryo-EM. Nat.Methods doi:10.1038/s41592-022-01693-y
2022 Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease. Biomolecules doi:10.3390/biom12050696
2022 Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease. Molecules doi:10.3390/molecules27206835
2022 Cryo-EM structures of staphylococcal IsdB bound to human hemoglobin reveal the process of heme extraction. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.2116708119
2021 Structural studies of hemoglobin from two flightless birds, ostrich and turkey: insights into their differing oxygen-binding properties. Acta Crystallogr D Struct Biol doi:10.1107/S2059798321003417
2021 PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease. J.Med.Chem. doi:10.1021/acs.jmedchem.0c01518
2021 MetAP2 inhibition modifies hemoglobin S to delay polymerization and improves blood flow in sickle cell disease. Blood Adv doi:10.1182/bloodadvances.2020003670
2021 Effect of X-ray free-electron laser-induced shockwaves on haemoglobin microcrystals delivered in a liquid jet. Nat Commun doi:10.1038/s41467-021-21819-8
2021 Crystal structure of hemoglobin from mouse (Mus musculus) compared with those from other small animals and humans. Acta Crystallogr.,Sect.F doi:10.1107/S2053230X2100306X
2021 A cryo-electron microscopy support film formed by 2D crystals of hydrophobin HFBI. Nat Commun doi:10.1038/s41467-021-27596-8
2020 Direct observation of ligand migration within human hemoglobin at work. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.1913663117
2020 Biodistribution PET/CT Study of Hemoglobin-DFO-89Zr Complex in Healthy and Lung Tumor-Bearing Mice. Int J Mol Sci doi:10.3390/ijms21144991
2020 Exploration of Structure-Activity Relationship of Aromatic Aldehydes Bearing Pyridinylmethoxy-Methyl Esters as Novel Antisickling Agents. J.Med.Chem. doi:10.1021/acs.jmedchem.0c01287
2020 VZHE-039, a novel antisickling agent that prevents erythrocyte sickling under both hypoxic and anoxic conditions. Sci Rep doi:10.1038/s41598-020-77171-2
2020 The nitrosoamphetamine metabolite is accommodated in the active site of human hemoglobin: Spectroscopy and crystal structure. J.Inorg.Biochem. doi:10.1016/j.jinorgbio.2020.111262
2020 Genetically engineered haemoglobin wrapped covalently with human serum albumins as an artificial O2carrier. J Mater Chem B doi:10.1039/c9tb02184a