CODSWALLOP

High affinity nerve growth factor receptor

Homo sapiens · seed P04629 · 796 aa · family defined as ≥30% identity to that seed · compiled 07 October 2026

Open in CODSWALLOP UniProt P04629 RCSB by accession PDBe-KB AlphaFold DB InterPro CATH 2.30.30.40 CATH 3.30.200.20 CATH 3.30.505.10 CATH 1.10.510.10 SCOP 8069207 SCOP 8041589 SCOP 8069229 SCOP 8069235 SCOP 8034606 SCOP 8069197 SCOP 8040167 SCOP 8091373 SCOP 8069247 SCOP 8036660 SCOP 8034200 SCOP 8040008 SCOP 8036668 SCOP 8034993 SCOP 8036665 SCOP 8033424 SCOP 8039520 SCOP 8069205 SCOP 8069187 SCOP 8039582 SCOP 8069237 SCOP 8032830 SCOP 8040157 SCOP 8043964 SCOP 8043784 SCOP 8036479 SCOP 8069199 SCOP 8036040 SCOP 8035661 SCOP 8036656 SCOP 8032837 RCSB 4AOJ PDBe

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.

1,986Entries 1,998Entities 784Constructs 10Organisms 1,759Ligand-bound
0.98 ÅBest res.
2.19 ÅMedian res.

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

The reference structure

4AOJ, 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 4AOJ
4AOJ 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.

13987961984 constructs

Constructs, most-used first

784 distinct constructs across 1,986 entries. 1,836 polymer entities differ from the UniProt canonical sequence in some way, 152 carry a recognised expression tag and 6 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
61 306 0.98 6Q7D residues 595-900; E595G
32 286 1.80 7WF5 residues 248-533; S248G, K249H, P250M
29 331 2.10 5CAS residues 694-1024; P694G, T790M, L858R +5 more
26 327 1.50 3POZ residues 696-1022
25 327 1.50 8PQD residues 548-934; 2 internal deletions; L548G, Q549S, K550M +25 more
21 271 1.10 6DI1 residues 389-659
21 331 1.83 7JXQ residues 692-1022; L692G, T693S, P694T +2 more
21 454 1.65 5H0B residues 72-526; 1 internal deletion; I73A, R74M, E75G +6 more
18 291 1.40 4FYO His6; residues 353-635; A353M, D354A, P355L
17 299 1.47 6ZCS His6; residues 343-635
17 309 1.63 5EW8 residues 457-765; L457G, C488A, C584S
15 276 1.55 4D4R residues 411-686
15 314 1.64 7DUA residues 700-1013; M700G, E701P, N702L +2 more
15 321 1.29 6FEX His6; residues 593-913; 1 internal deletion
15 327 1.73 4CMT residues 1085-1411; T1085M, S1086A, T1087H +5 more
14 285 1.99 3AC1 residues 225-509
14 333 1.50 6TFV residues 690-1022; E690G, P691S, L692H +4 more
14 1370 3.24 8X06 1 internal deletion
13 298 1.74 7AB0 residues 567-864; L567G, G568S, V569H +5 more
12 290 1.50 8XQ1 His8; residues 356-635
12 313 1.90 3BRB residues 556-864; 4-residue insertion after 569; C556M, R557G, R558S +8 more
12 314 1.60 3EWH residues 815-1178; 1 internal deletion; C817A, V916T, T940V +7 more
12 329 1.33 5UG9 residues 694-1022; P694G, T790M, L858R +1 more
11 302 1.65 2VWX residues 598-899; Y774E
11 309 1.75 4XMO residues 1048-1356; V1352H, N1353H, A1354H +2 more

Showing the 25 most-used of 784.

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".

E535D 70% A553D 70% A642E 68% D679E 68% H571N 68% K609Q 68% S552K 67% Y701D 67% E755D 67% F721M 67% A785T 66% D556E 66% S672A 66% C656V 64% K703I 63% I505L 63% A520Q 62% I675A 62% P606D 62% A631C 61% L567F 61% V634I 61% G684Q 61% P534K 60% L622I 59% L689F 59% L624S 59% D674G 59% A500S 59% G623T 59%

What it assembles into

Oligomeric stateChainsEntriesShare
monomeric1 1,686 84.9%
dimeric2 209 10.5%
tetrameric4 42 2.1%
hexameric6 21 1.1%
trimeric3 16 0.8%
pentameric5 4 0.2%
octameric8 4 0.2%
dodecameric12 2 0.1%

1,166 entries have the depositor's assembly corroborated by PISA, 736 carry the depositor's word alone and 84 were assigned by PISA where the depositor gave none. The middle figure is not a disagreement: PISA may have returned nothing or never run. 67 entries carry more than one assembly with different chain counts, so they have no single answer to quote: 1GAG, 1K9A, 1OPL, 1P4O, 1PKG, 1WWA, 2G2F, 2G2I, 2RFE, 2ZM3, 3B2T, 3C4F, 3CLY, 3EFJ, 3EFK, 3EQP, 3EQR, 3ETA, 3F5P, 3G0F.

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.

CATHSH3 DomainsPhosphorylase Kinase; domaSH2 domainTransferase(PhosphotransfeSCOP2BProtein kinase-like (PK-liSH3-domainProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liL domain-likeProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liSH2 domainProtein kinase-like (PK-liGrowth factor receptor dom1398796
DomainSourceSpan (seed)Chains
SH3 DomainsCATH 2.30.30.40 497–558 31
Phosphorylase Kinase; domain 1CATH 3.30.200.20 516–611 1,417
SH2 domainCATH 3.30.505.10 559–660 43
Transferase(Phosphotransferase) domain 1CATH 1.10.510.10 612–796 1,471
Protein kinase-like (PK-like)SCOP2B 8069207 495–796 25
SH3-domainSCOP2B 8041589 498–558 23
Protein kinase-like (PK-like)SCOP2B 8069229 502–796 63
Protein kinase-like (PK-like)SCOP2B 8069235 502–790 54
Protein kinase-like (PK-like)SCOP2B 8034606 505–796 20
Protein kinase-like (PK-like)SCOP2B 8069197 506–778 22
Protein kinase-like (PK-like)SCOP2B 8040167 510–781 25
Protein kinase-like (PK-like)SCOP2B 8091373 511–781 46

What binds it

ANP ANP63 entries ACP ACP29 entries STI STI24 entries NAG NAG20 entries STU STU19 entries 1N1 1N117 entries ADP ADP16 entries 0LI 0LI13 entries YY3 YY310 entries VGH VGH9 entries DB8 DB87 entries Q6K Q6K7 entries
ComponentClassNameEntriesBest (Å)
SO4ion Sulfate Ion 316 1.21
CLion Chloride Ion 166 1.29
EDOcryoprotectant 1,2-Ethanediol 163 1.04
GOLcryoprotectant Glycerol 142 1.30
MGion Magnesium Ion 103 1.25
DMScryoprotectant Dimethyl Sulfoxide 73 1.11
ANPcofactor Phosphoaminophosphonic Acid-Adenylate Ester 63 1.25
ACPcofactor Phosphomethylphosphonic Acid Adenylate Ester 29 1.75
CAion Calcium Ion 24 1.70
STIligand 4-(4-Methyl-Piperazin-1-Ylmethyl)-N-[4-Methyl-3-(4-Pyridin-3-Yl- 24 1.57
MESbuffer 2-(N-Morpholino)-Ethanesulfonic Acid 24 1.11
NAion Sodium Ion 23 1.40
PO4ion Phosphate Ion 22 1.60
FMTbuffer Formic Acid 21 1.65
NAGcofactor 2-Acetamido-2-Deoxy-Beta-D-Glucopyranose 20 1.84
STUligand Staurosporine 19 1.75
IODion Iodide Ion 19 1.29
IMDbuffer Imidazole 18 1.15
1N1ligand N-(2-Chloro-6-Methylphenyl)-2-({6-[4-(2-Hydroxyethyl)piperazin-1 17 1.16
ADPcofactor Adenosine-5'-Diphosphate 16 1.52

How it crystallises

Parsed from the free text 1,835 depositors typed into _exptl_crystal_grow.pdbx_details, out of 1,858 entries that recorded anything at all. Median pH 7.1 (range 0.0 to 10.5).

Precipitants

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

Buffers

HEPES × Tris × MES × Citrate × Bis-Tris × Sodium acetate × Sodium cacodylate × Bis-Tris propane × Imidazole × Phosphate × Glycine × CAPS × Succinate × CHES ×

Which entries to trust

1,985 entries carry a wwPDB validation report: 548 clean, 964 worth a check and 473 with something to explain. Median clashscore 4.51, median RSRZ outliers 6.01%, median R-free minus R-work 0.039. 1,918 have released structure factors.

Across species

OrganismEntriesBest (Å)Ligand-boundSeed covered
Homo sapiens1,798 0.98 1606 96%
Gallus gallus103 1.55 90 68%
Mus musculus74 1.22 52 38%
Drosophila melanogaster4 3.60 4 36%
Bos taurus2 1.60 2 34%
Rattus norvegicus2 2.05 0 38%
synthetic construct2 2.05 2 34%
Monosiga brevicollis1 1.95 1 35%
Spodoptera frugiperda1 2.59 1 35%
Schistosoma mansoni1 3.07 1 35%

Seed sequence

796 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

1MLRGGRRGQL GWHSWAAGPG SLLAWLILAS AGAAPCPDAC CPHGSSGLRC TRDGALDSLH
61HLPGAENLTE LYIENQQHLQ HLELRDLRGL GELRNLTIVK SGLRFVAPDA FHFTPRLSRL
121NLSFNALESL SWKTVQGLSL QELVLSGNPL HCSCALRWLQ RWEEEGLGGV PEQKLQCHGQ
181GPLAHMPNAS CGVPTLKVQV PNASVDVGDD VLLRCQVEGR GLEQAGWILT ELEQSATVMK
241SGGLPSLGLT LANVTSDLNR KNVTCWAEND VGRAEVSVQV NVSFPASVQL HTAVEMHHWC
301IPFSVDGQPA PSLRWLFNGS VLNETSFIFT EFLEPAANET VRHGCLRLNQ PTHVNNGNYT
361LLAANPFGQA SASIMAAFMD NPFEFNPEDP IPVSFSPVDT NSTSGDPVEK KDETPFGVSV
421AVGLAVFACL FLSTLLLVLN KCGRRNKFGI NRPAVLAPED GLAMSLHFMT LGGSSLSPTE
481GKGSGLQGHI IENPQYFSDA CVHHIKRRDI VLKWELGEGA FGKVFLAECH NLLPEQDKML
541VAVKALKEAS ESARQDFQRE AELLTMLQHQ HIVRFFGVCT EGRPLLMVFE YMRHGDLNRF
601LRSHGPDAKL LAGGEDVAPG PLGLGQLLAV ASQVAAGMVY LAGLHFVHRD LATRNCLVGQ
661GLVVKIGDFG MSRDIYSTDY YRVGGRTMLP IRWMPPESIL YRKFTTESDV WSFGVVLWEI
721FTYGKQPWYQ LSNTEAIDCI TQGRELERPR ACPPEVYAIM RGCWQREPQQ RHSIKDVHAR
781LQALAQAPPV YLDVLG

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 Molecular Basis of c‐MET Inhibition by Approved Small Molecule Drugs: A Structural Perspective. Acs Med.Chem.Lett. doi:10.1021/acsmedchemlett.5c00713
2026 Discovery of Covalent Ligands with AlphaFold3. J.Am.Chem.Soc. doi:10.1021/jacs.5c22222
2026 Discovery of an ITK and TRK kinase inhibitor for the potential topical treatment of atopic dermatitis. Nat Commun doi:10.1038/s41467-026-70000-6
2026 Strategic Use of Benzylic Alcohols Reveals Cryptic Hydrogen-Bonding Interactions: Discovery of HBC-12551 as a Potent Noncovalent Bruton's Tyrosine Kinase Inhibitor. J.Med.Chem. doi:10.1021/acs.jmedchem.5c02785
2026 Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors. Cancer Discov doi:10.1158/2159-8290.CD-26-0251
2026 Design and Synthesis of BLU-654, a Potent and Selective Mutant KIT V654A Inhibitor for the Treatment of Imatinib-Resistant GIST. J.Med.Chem. doi:10.1021/acs.jmedchem.5c03554
2026 Late-stage functionalization with strain-release warheads enables tunable covalent inhibition. Science doi:10.1126/science.adx7219
2026 Discovery of the Orally Bioavailable Isoform Selective Janus Kinase 1 (JAK1) Compound Povorcitinib (INCB054707) for the Treatment of Inflammatory and Autoimmune Diseases. J.Med.Chem. doi:10.1021/acs.jmedchem.5c03753
2026 Janus kinase 2 activation loop as a regulator of catalysis and trans-activation. Int.J.Biol.Macromol. doi:10.1016/j.ijbiomac.2026.153276
2026 Structure-based scaffold hopping reveals strategies to overcome oncogenic KIT and PDGFRA mutation-driven drug-resistance in GIST. Nat Commun doi:10.1038/s41467-026-76340-7
2026 Structure-Based Design of a Novel Covalent 4-(1-Methylindol-3-yl)pyrimidin-2-amine Series Targeting FGFR2 Resistance Mutations. J.Med.Chem. doi:10.1021/acs.jmedchem.6c00514
2026 Structure-Based Design of 4-(1-Methyl-1 H -indol-3-yl)pyrimidin-2-amine Derivatives as the First Covalent FGFR3 Selective Inhibitors. J.Med.Chem. doi:10.1021/acs.jmedchem.5c02552
2026 Design, Synthesis, and Biological Evaluation of the First Novel Macrocycle-Based FGFR Inhibitors That Overcome Clinically Acquired Resistance. J.Med.Chem. doi:10.1021/acs.jmedchem.5c02462
2026 A Journey through Scaffolds: Indolines, Pyrrolidines, and Azetidines in the Quest for Inhaled DDR Inhibitors for IPF. J.Med.Chem. doi:10.1021/acs.jmedchem.5c02830
2026 Structural Studies of Fourth-Generation EGFR Inhibitors Reveal Insights into Selective T790M and C797S Targeting. Acs Med.Chem.Lett. doi:10.1021/acsmedchemlett.5c00725
2026 Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer. Cancer Discov doi:10.1158/2159-8290.CD-25-0605
2026 Leveraging Structure-Based Design to Overcome Class III RTK Off-Target Activity in the Development of Selective Wild-Type KIT Inhibitors J.Med.Chem. doi:10.1021/acs.jmedchem.6c01334
2026 An S752D activation loop mutation dynamically primes Muscle-Specific Kinase for activation. Biochem.J. doi:10.1042/BCJ20260159
2026 Fyn-Saracatinib Complex Structure Reveals an Active State-like Conformation. Int J Mol Sci doi:10.3390/ijms27031143
2026 Identification of an Inhaled Pulmonary Selective PDGFR Inhibitor with Sustained Target Engagement. J Aerosol Med Pulm Drug Deliv doi:10.1177/19412711261449635
2026 TAS3351 is a brain penetrable EGFR-TKI that overcomes T790M and C797S resistant mutations. Commun Med (Lond) doi:10.1038/s43856-026-01546-1
2026 Covalent Alkynylpyridopyrimidinones Targeting Cysteine 775 of the Epidermal Growth Factor Receptor Overcome Resistance to Current Therapies. J.Med.Chem. doi:10.1021/acs.jmedchem.5c02924
2026 Discovery of a Potent, Orally Bioavailable Small-Molecule Inhibitor of Wildtype KIT with Exceptionally High Kinome Selectivity. J.Med.Chem. doi:10.1021/acs.jmedchem.6c00898
2026 Discovery of 2H-Pyrrolo[3,4‐ c ]pyridin-3-one Derivatives as Type-III c‐MET Inhibitors Enabled by Free-Energy Perturbation Calculations. Acs Med.Chem.Lett. doi:10.1021/acsmedchemlett.6c00158
2026 Structural insights into the activation of the chicken ROS1 receptor by the NEL/NICOL ligand complex. Nat Commun doi:10.1038/s41467-026-69942-8
2026 TRI-611, a selective, brain-penetrant molecular glue degrader of ALK. Nature doi:10.1038/s41586-026-10998-3
2026 Design, synthesis and biological evaluation of 2,4,5-trisubstituted 7H-Pyrrolo[2,3-d]pyrimidine derivatives as potent EGFR tyrosine kinase inhibitors against the C797S acquired resistance mutation. Bioorg.Med.Chem. doi:10.1016/j.bmc.2026.118679
2026 A Dichloropropionamide-Substituted Diaminopyrimidine EGFR-TKI Overcomes Osimertinib Resistance in NSCLC via Dual Anchoring at Ser797 and Met793. J.Med.Chem. doi:10.1021/acs.jmedchem.5c02807
2026 The role of kinase domain dimerization in EGFR activation. Structure doi:10.1016/j.str.2025.11.017
2026 Mechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy. Nat Commun doi:10.1038/s41467-026-69884-1
2026 Enozertinib Is a Selective, Brain-Penetrant EGFR Inhibitor for Treating Non-Small Cell Lung Cancers with EGFR Exon 20 and Atypical Mutations. Cancer Res. doi:10.1158/0008-5472.CAN-25-3502
2026 Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2. Nat Commun doi:10.1038/s41467-026-73851-1
2025 Electron-density-informed effective and reliable de novo molecular design and optimization with ED2Mol Nat Mach Intell doi:10.1038/s42256-025-01095-7
2025 STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models. Clin.Cancer Res. doi:10.1158/1078-0432.CCR-24-3833
2025 Design, Synthesis and Biological Evaluation of 7-(1-Methyl-1 H -indole-3-yl)-5 H -pyrrolo[2,3- b ]pyrazine Derivatives as Novel Covalent pan-FGFR Inhibitors to Overcome Clinical Resistance. J.Med.Chem. doi:10.1021/acs.jmedchem.5c01594
2025 Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer. J.Med.Chem. doi:10.1021/acs.jmedchem.4c02377
2025 Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations. J.Med.Chem. doi:10.1021/acs.jmedchem.4c02811
2025 Profiling and Optimizing Targeted Covalent Inhibitors through EGFR-Guided Studies. J.Med.Chem. doi:10.1021/acs.jmedchem.5c01661
2025 Factors affecting irreversible inhibition of EGFR and influence of chirality on covalent binding. Commun Chem doi:10.1038/s42004-025-01501-6
2025 Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects. J.Am.Chem.Soc. doi:10.1021/jacs.5c07063