CODSWALLOP

Acetylcholinesterase

Homo sapiens · seed P22303 · 614 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.

562Entries 569Entities 152Constructs 29Organisms 481Ligand-bound
1.10 ÅBest res.
2.40 ÅMedian res.

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

The reference structure

6O5V, 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 6O5V
6O5V 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.

1307614566 constructs

Constructs, most-used first

152 distinct constructs across 562 entries. 529 polymer entities differ from the UniProt canonical sequence in some way, 28 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
61 529 1.85 6ZWI residues 29-557; N45Q, N483Q, N509Q +1 more
53 537 1.80 1EA5 residues 22-558
37 542 2.00 4M0E residues 33-574
37 543 2.05 2HA2 residues 32-574
31 548 2.10 4B82 residues 32-581; 1 internal deletion; D575A, E581P
30 543 2.05 1W6R residues 22-564
20 550 2.15 6O5V residues 29-578; V29G, G30P, A31L
13 570 1.95 4FNG M364L, I419F, A472T +3 more
12 532 1.85 7B38 residues 25-556
11 577 1.53 5CH5 His6; D83A, M364L, I419F +4 more
8 532 1.86 5A7F residues 21-553; 1 internal deletion
8 534 2.10 5EI5 residues 23-556
8 543 2.60 2XUI residues 32-574; Y368A
7 586 1.75 7AIS matches the canonical sequence
6 529 2.10 2WIJ residues 29-557; N45Q, N483Q, N509Q
6 565 1.79 6G1U residues 22-586
5 527 2.10 2XQF residues 31-557; N45Q, N483Q, N509Q +1 more
5 547 1.75 6H1A His8; residues 17-553; V17L, A18Y, S19F +4 more
5 549 2.18 1LPM matches the canonical sequence
5 557 1.90 6QAA residues 1-557; H2D, N45Q, N483Q +2 more
5 870 3.22 8G7Z 3C/PreScission site; 1 internal deletion; 17-residue insertion after 12; M1G, W2A, L3P +5 more
4 529 2.10 2XMB residues 29-557; N45Q, G145H, N483Q +2 more
4 529 2.60 6F7Q residues 29-557
4 540 1.79 9D1K matches the canonical sequence
4 540 2.45 7E3H residues 35-574

Showing the 25 most-used of 152.

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".

G251S 69% P248G 68% L355T 68% S340P 68% Q97P 68% T280V 68% A538E 68% R196Q 68% V362N 68% Y368F 68% P477I 68% Q171Y 68% R307K 68% Y136A 67% Y101Q 67% V257I 67% G265C 67% H315N 67% E112S 67% Q530S 67% Q452F 67% R44K 67% K54T 67% I485V 67% H318N 66% Q505R 66% T269V 66% A302H 66% I347L 66% S430D 66%

What it assembles into

Oligomeric stateChainsEntriesShare
dimeric2 317 56.4%
monomeric1 186 33.1%
tetrameric4 18 3.2%
octameric8 18 3.2%
trimeric3 14 2.5%
hexameric6 5 0.9%
pentameric5 4 0.7%

332 entries have the depositor's assembly corroborated by PISA, 202 carry the depositor's word alone and 28 were assigned by PISA where the depositor gave none. The middle figure is not a disagreement: PISA may have returned nothing or never run. 23 entries carry more than one assembly with different chain counts, so they have no single answer to quote: 1F8U, 1KU6, 1LPN, 1LPP, 1P0I, 1P0P, 1U4N, 1XLU, 1XLV, 1XLW, 2H7C, 3DJY, 3DKK, 3K9B, 3O9M, 3RAR, 3VKF, 4AQD, 4BDT, 4FNG.

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.

CATHAlpha/Beta hydrolase fold,SCOP2Balpha/beta-Hydrolasesalpha/beta-Hydrolasesalpha/beta-Hydrolasesalpha/beta-Hydrolasesalpha/beta-Hydrolasesalpha/beta-Hydrolasesalpha/beta-Hydrolasesalpha/beta-Hydrolasesalpha/beta-Hydrolases1307614
DomainSourceSpan (seed)Chains
Alpha/Beta hydrolase fold, catalytic domainCATH 3.40.50.1820 38–572 450
alpha/beta-HydrolasesSCOP2B 8042208 32–573 96
alpha/beta-HydrolasesSCOP2B 8032481 36–573 75
alpha/beta-HydrolasesSCOP2B 8086463 36–572 5
alpha/beta-HydrolasesSCOP2B 8032473 38–569 123
alpha/beta-HydrolasesSCOP2B 8033793 38–563 109
alpha/beta-HydrolasesSCOP2B 8032490 56–587 6
alpha/beta-HydrolasesSCOP2B 8042176 59–590 20
alpha/beta-HydrolasesSCOP2B 8032600 77–610 7
alpha/beta-HydrolasesSCOP2B 8071846 109–614 6

What binds it

NAG NAG369 entries SIA SIA29 entries HI6 HI617 entries PG0 PG017 entries DPF DPF16 entries VX VX14 entries DEP DEP10 entries TOE TOE9 entries P15 P158 entries TZ4 TZ46 entries FUC FUC6 entries GNT GNT5 entries
ComponentClassNameEntriesBest (Å)
NAGcofactor 2-Acetamido-2-Deoxy-Beta-D-Glucopyranose 369 1.48
SO4ion Sulfate Ion 146 1.50
CLion Chloride Ion 129 1.75
GOLcryoprotectant Glycerol 105 1.30
EDOcryoprotectant 1,2-Ethanediol 58 1.10
PEGcryoprotectant Di(Hydroxyethyl)ether 55 1.10
P6Gcryoprotectant Hexaethylene Glycol 53 1.79
MESbuffer 2-(N-Morpholino)-Ethanesulfonic Acid 51 1.86
NAion Sodium Ion 33 1.89
SIAcofactor N-Acetyl-Alpha-Neuraminic Acid 29 2.00
PGEcryoprotectant Triethylene Glycol 29 1.79
PG4cryoprotectant Tetraethylene Glycol 24 1.79
CAion Calcium Ion 23 2.00
NO3ion Nitrate Ion 21 2.00
ACTcryoprotectant Acetate Ion 19 1.10
HI6ligand 4-(Aminocarbonyl)-1-[({2-[(E)-(Hydroxyimino)methyl]pyridinium-1- 17 2.15
PG0ligand 2-(2-Methoxyethoxy)ethanol 17 2.10
DPFligand Diethyl Hydrogen Phosphate 16 1.53
UNXion Unknown Atom Or Ion 14 2.10
VXligand O-Ethylmethylphosphonic Acid Ester Group 14 2.10

How it crystallises

Parsed from the free text 504 depositors typed into _exptl_crystal_grow.pdbx_details, out of 530 entries that recorded anything at all. Median pH 6.5 (range 4.2 to 9.0).

Precipitants

PEG × Ammonium sulfate × Sodium chloride × Sodium citrate × Lithium sulfate × MPD × Magnesium chloride × Calcium chloride × Isopropanol × PEG (unspecified) ×

Buffers

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

Which entries to trust

562 entries carry a wwPDB validation report: 343 clean, 122 worth a check and 97 with something to explain. Median clashscore 6.44, median RSRZ outliers 1.69%, median R-free minus R-work 0.039. 538 have released structure factors.

Across species

OrganismEntriesBest (Å)Ligand-boundSeed covered
Homo sapiens228 1.48 211 100%
Tetronarce californica124 1.75 109 99%
Mus musculus109 2.00 104 95%
Lucilia cuprina38 1.10 23 82%
Anopheles gambiae7 1.79 5 89%
Diutina rugosa9 1.97 8 64%
Thermobifida fusca4 1.39 3 82%
Bos taurus4 1.60 3 88%
Rattus norvegicus4 1.80 3 88%
Alicyclobacillus acidocaldarius4 2.00 2 16%
Drosophila melanogaster4 2.15 3 88%
Bacillus subtilis3 1.50 0 82%

Seed sequence

614 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

1MRPPQCLLHT PSLASPLLLL LLWLLGGGVG AEGREDAELL VTVRGGRLRG IRLKTPGGPV
61SAFLGIPFAE PPMGPRRFLP PEPKQPWSGV VDATTFQSVC YQYVDTLYPG FEGTEMWNPN
121RELSEDCLYL NVWTPYPRPT SPTPVLVWIY GGGFYSGASS LDVYDGRFLV QAERTVLVSM
181NYRVGAFGFL ALPGSREAPG NVGLLDQRLA LQWVQENVAA FGGDPTSVTL FGESAGAASV
241GMHLLSPPSR GLFHRAVLQS GAPNGPWATV GMGEARRRAT QLAHLVGCPP GGTGGNDTEL
301VACLRTRPAQ VLVNHEWHVL PQESVFRFSF VPVVDGDFLS DTPEALINAG DFHGLQVLVG
361VVKDEGSYFL VYGAPGFSKD NESLISRAEF LAGVRVGVPQ VSDLAAEAVV LHYTDWLHPE
421DPARLREALS DVVGDHNVVC PVAQLAGRLA AQGARVYAYV FEHRASTLSW PLWMGVPHGY
481EIEFIFGIPL DPSRNYTAEE KIFAQRLMRY WANFARTGDP NEPRDPKAPQ WPPYTAGAQQ
541YVSLDLRPLE VRRGLRAQAC AFWNRFLPKL LSATDTLDEA ERQWKAEFHR WSSYMVHWKN
601QFDHYSKQDR CSDL

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 Structural and evolutionary constraints of organophosphate resistance in dipteran carboxylesterases. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.2517957123
2026 Potent and selective indole-based inhibitors targeting disease-transmitting mosquitoes. Rsc Med Chem doi:10.1039/d5md00797f
2026 Leveraging multitargeting BChE-MAO B inhibitors against microglia-related neuroinflammation: in vitro biological evaluation, structure-activity relationships, drug-like properties, and X-ray crystal complexes. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2026.118961
2026 Design, synthesis and evaluation of an uncharged broad spectrum quinoline-oxime hybrid for the reactivation of nerve agent-inhibited human acetylcholinesterase. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2026.119023
2026 Integrative structural and kinetic analysis of the molecular basis for reduced carbamate inhibition in atypical butyrylcholinesterase. Chem.Biol.Interact. doi:10.1016/j.cbi.2026.112134
2026 An improved nerve agent bioscavenger based on the fast self-reactivation mechanism of porcine butyrylcholinesterase. Protein Sci. doi:10.1002/pro.70467
2026 Dual Inhibitors J.Med.Chem. doi:10.1021/acs.jmedchem.6c01461
2026 Structure-Guided Design and Synthesis of Selective Butyrylcholinesterase Inhibitors J.Mol.Struct. doi:10.1016/j.molstruc.2026.145611
2026 Structures of distinct human acetylcholinesterase tetramer forms in complex with synaptic anchoring proteins Structure doi:10.1016/j.str.2026.08.016
2026 Weaker neuroligin 2-neurexin beta 1 interaction tethers membranes and recruits gephyrin at membrane junctions through clustering. Sci Adv doi:10.1126/sciadv.ads9732
2025 Heat-sterilizable antibody mimics designed on the cold shock protein scaffold from hyperthermophile Thermotoga maritima. Protein Sci. doi:10.1002/pro.70018
2025 Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease. Chem.Biol.Interact. doi:10.1016/j.cbi.2025.111670
2025 N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors. Chem.Biol.Interact. doi:10.1016/j.cbi.2025.111681
2025 Understanding the molecular mechanism of fumonisin esterases by kinetic and structural studies. Food Chem doi:10.1016/j.foodchem.2025.143110
2025 Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38 alpha Mitogen-Activated Protein Kinase Inhibitors. J.Med.Chem. doi:10.1021/acs.jmedchem.5c00933
2025 Kinetic and structural evidence for specific DMSO interference with reversible binding of uncharged bis-oximes to hAChE and their reactivation kinetics of OP-hAChE. Chem.Biol.Interact. doi:10.1016/j.cbi.2025.111649
2025 Multifunctional, Fluorene-Based Modulator of Cholinergic and GABAergic Neurotransmission as a Novel Drug Candidate for Palliative Treatment of Alzheimer's Disease. Angew.Chem.Int.Ed.Engl. doi:10.1002/anie.202420510
2025 The product of Ellman's reaction inhibits cholinesterases. Protein Sci. doi:10.1002/pro.70371
2025 Dual cholinergic modulation in dementia: Quinuclidine carbamates targeting butyrylcholinesterase and alpha 7 nicotinic receptor. Chem.Biol.Interact. doi:10.1016/j.cbi.2025.111830
2025 Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease. J.Med.Chem. doi:10.1021/acs.jmedchem.5c00577
2024 The study of halogen effect on the reactivity of the serine-targeting covalent warheads. Front Chem doi:10.3389/fchem.2024.1504453
2024 Disentangling the formation, mechanism, and evolvement of the covalent methanesulfonyl fluoride acetylcholinesterase adduct: Insights into an aged-like inactive complex susceptible to reactivation by a combination of nucleophiles. Protein Sci. doi:10.1002/pro.4977
2024 Enzyme Dynamics Determine the Potency and Selectivity of Inhibitors Targeting Disease-Transmitting Mosquitoes. Acs Infect Dis. doi:10.1021/acsinfecdis.4c00531
2023 Rapid discovery and crystallography study of highly potent and selective butylcholinesterase inhibitors based on oxime-containing libraries and conformational restriction strategies. Bioorg.Chem. doi:10.1016/j.bioorg.2023.106465
2023 8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases. Acta Pharm Sin B doi:10.1016/j.apsb.2023.01.013
2023 Pseudo-irreversible butyrylcholinesterase inhibitors: Structure-activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2022.115048
2023 Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2023.115135
2023 Structure of an antennally-expressed carboxylesterase suggests lepidopteran odorant degrading enzymes are broadly tuned Curr Res Insect Sci doi:10.1016/j.cris.2023.100062
2023 Highly selective butyrylcholinesterase inhibitors related to Amaryllidaceae alkaloids - Design, synthesis, and biological evaluation. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2023.115301
2023 High-resolution structural-omics of human liver enzymes. Cell Rep doi:10.1016/j.celrep.2023.112609
2022 Structural Insights into (Tere)phthalate-Ester Hydrolysis by a Carboxylesterase and Its Role in Promoting PET Depolymerization Acs Catalysis doi:10.1021/acscatal.2c03772
2022 The Crystal Structure of Mouse Ces2c, a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1. Int J Mol Sci doi:10.3390/ijms232113101
2022 From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series. Eur.J.Med.Chem. doi:10.1016/j.ejmech.2022.114248
2022 Structural and dynamic effects of paraoxon binding to human acetylcholinesterase by X-ray crystallography and inelastic neutron scattering. Structure doi:10.1016/j.str.2022.09.006
2022 Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase. Chemistry doi:10.1002/chem.202200678
2022 Crystal structure of human acetylcholinesterase in complex with tacrine: Implications for drug discovery Int.J.Biol.Macromol. doi:10.1016/j.ijbiomac.2022.05.009
2022 Grid-Type Quaternary Metallosupramolecular Compounds Inhibit Human Cholinesterases through Dynamic Multivalent Interactions. Chembiochem doi:10.1002/cbic.202200456
2022 Dual Reversible Coumarin Inhibitors Mutually Bound to Monoamine Oxidase B and Acetylcholinesterase Crystal Structures. Acs Med.Chem.Lett. doi:10.1021/acsmedchemlett.2c00001
2022 A New Class of Bi- and Trifunctional Sugar Oximes as Antidotes against Organophosphorus Poisoning. J.Med.Chem. doi:10.1021/acs.jmedchem.1c01748
2022 Cryo-EM structure of native human thyroglobulin. Nat Commun doi:10.1038/s41467-021-27693-8