CODSWALLOP

Tyrosine-protein kinase JAK1

Homo sapiens · seed P23458 · 1154 aa · family defined as ≥30% identity to that seed · compiled 07 October 2026

Open in CODSWALLOP UniProt P23458 RCSB by accession PDBe-KB AlphaFold DB InterPro CATH 3.30.200.20 CATH 3.30.505.10 CATH 1.10.510.10 SCOP 8069255 SCOP 8039582 SCOP 8069261 SCOP 8069259 SCOP 8040008 SCOP 8091373 SCOP 8034200 SCOP 8069207 SCOP 8069247 SCOP 8069237 SCOP 8036660 SCOP 8069197 SCOP 8034606 SCOP 8043964 SCOP 8034993 SCOP 8040167 SCOP 8036668 SCOP 8039520 SCOP 8040157 SCOP 8069205 SCOP 8043784 SCOP 8069187 SCOP 8069199 SCOP 8036040 SCOP 8032830 SCOP 8032837 RCSB 6N7A 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.

1,814Entries 1,825Entities 710Constructs 8Organisms 1,639Ligand-bound
1.07 ÅBest res.
2.15 ÅMedian res.

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

The reference structure

6N7A, 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 6N7A
6N7A 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.

157711541743 constructs

Constructs, most-used first

710 distinct constructs across 1,814 entries. 1,745 polymer entities differ from the UniProt canonical sequence in some way, 165 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
29 289 1.40 8BA3 residues 536-826; 1 internal deletion; W659A, W777A, F794H +11 more
29 331 2.10 5CAS residues 694-1024; P694G, T790M, L858R +5 more
28 302 1.64 6N77 residues 853-1154; P853G
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
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
15 308 1.90 6VGL residues 825-1132; M825H, R826H, I827H +12 more
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
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
11 309 1.75 4XMO residues 1048-1356; V1352H, N1353H, A1354H +2 more
11 328 1.76 6WXN residues 695-1022; T790M, V948R
11 330 1.70 3W33 residues 693-1022; T693G, P694A, S695M
10 269 1.35 9NWX residues 352-620; R352G, Y353S, K596R

Showing the 25 most-used of 710.

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".

D895I 69% N900K 69% I928V 69% T1070L 69% L1153A 69% A984C 69% K972R 68% P1118D 67% V856A 66% R997K 66% K1130D 66% G898K 66% I975L 65% F870K 65% I943V 65% I878G 65% Y1077F 65% E890Y 64% S857G 64% P960A 64% L1127I 63% D921E 63% M956T 63% Y894W 62% E871P 60% K1026R 60% T945L 59% D899E 59% K876T 59% L932V 59%

What it assembles into

Oligomeric stateChainsEntriesShare
monomeric1 1,545 85.2%
dimeric2 209 11.5%
tetrameric4 30 1.7%
trimeric3 12 0.7%
hexameric6 11 0.6%
pentameric5 4 0.2%
octameric8 3 0.2%

1,064 entries have the depositor's assembly corroborated by PISA, 680 carry the depositor's word alone and 70 were assigned by PISA where the depositor gave none. The middle figure is not a disagreement: PISA may have returned nothing or never run. 71 entries carry more than one assembly with different chain counts, so they have no single answer to quote: 1GAG, 1K9A, 1OPL, 1P4O, 1PKG, 2G2F, 2G2I, 2RFE, 2ZM3, 3B2T, 3C4F, 3CLY, 3EFJ, 3EFK, 3EQP, 3EQR, 3ETA, 3F5P, 3G0F, 3GOP.

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.

CATHPhosphorylase Kinase; domaSH2 domainTransferase(PhosphotransfeSCOP2BProtein 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-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liProtein kinase-like (PK-liL domain-likeGrowth factor receptor dom15771154
DomainSourceSpan (seed)Chains
Phosphorylase Kinase; domain 1CATH 3.30.200.20 881–974 1,265
SH2 domainCATH 3.30.505.10 888–996 21
Transferase(Phosphotransferase) domain 1CATH 1.10.510.10 975–1154 1,308
Protein kinase-like (PK-like)SCOP2B 8069255 867–1154 46
Protein kinase-like (PK-like)SCOP2B 8039582 867–1129 27
Protein kinase-like (PK-like)SCOP2B 8069261 869–1154 28
Protein kinase-like (PK-like)SCOP2B 8069259 870–1154 41
Protein kinase-like (PK-like)SCOP2B 8040008 872–1129 123
Protein kinase-like (PK-like)SCOP2B 8091373 872–1142 46
Protein kinase-like (PK-like)SCOP2B 8034200 872–1148 20
Protein kinase-like (PK-like)SCOP2B 8069207 875–1154 25
Protein kinase-like (PK-like)SCOP2B 8069247 878–1154 109

What binds it

ANP ANP58 entries ACP ACP27 entries STI STI22 entries ADP ADP17 entries 1N1 1N112 entries 0LI 0LI12 entries STU STU11 entries PHU PHU11 entries YY3 YY310 entries ATP ATP8 entries Q6K Q6K7 entries IZA IZA6 entries
ComponentClassNameEntriesBest (Å)
SO4ion Sulfate Ion 301 1.21
GOLcryoprotectant Glycerol 156 1.30
CLion Chloride Ion 150 1.29
EDOcryoprotectant 1,2-Ethanediol 144 1.07
MGion Magnesium Ion 96 1.25
DMScryoprotectant Dimethyl Sulfoxide 74 1.11
ANPcofactor Phosphoaminophosphonic Acid-Adenylate Ester 58 1.25
ACPcofactor Phosphomethylphosphonic Acid Adenylate Ester 27 1.80
NAion Sodium Ion 27 1.40
MESbuffer 2-(N-Morpholino)-Ethanesulfonic Acid 23 1.11
STIligand 4-(4-Methyl-Piperazin-1-Ylmethyl)-N-[4-Methyl-3-(4-Pyridin-3-Yl- 22 1.57
ACTcryoprotectant Acetate Ion 22 1.21
FMTbuffer Formic Acid 21 1.65
PO4ion Phosphate Ion 19 1.60
IODion Iodide Ion 19 1.29
PEGcryoprotectant Di(Hydroxyethyl)ether 19 1.13
ADPcofactor Adenosine-5'-Diphosphate 17 1.52
IMDbuffer Imidazole 17 1.15
1N1ligand N-(2-Chloro-6-Methylphenyl)-2-({6-[4-(2-Hydroxyethyl)piperazin-1 12 1.54
0LIligand 3-(Imidazo[1,2-B]pyridazin-3-Ylethynyl)-4-Methyl-N-{4-[(4-Methyl 12 1.85

How it crystallises

Parsed from the free text 1,698 depositors typed into _exptl_crystal_grow.pdbx_details, out of 1,715 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 malonate × Sodium formate × PEG (unspecified) × Ethanol × Calcium chloride × Jeffamine ×

Buffers

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

Which entries to trust

1,814 entries carry a wwPDB validation report: 511 clean, 893 worth a check and 410 with something to explain. Median clashscore 4.08, median RSRZ outliers 5.73%, median R-free minus R-work 0.039. 1,770 have released structure factors.

Across species

OrganismEntriesBest (Å)Ligand-boundSeed covered
Homo sapiens1,728 1.07 1564 98%
Mus musculus55 1.22 51 100%
Gallus gallus23 1.55 18 24%
Bos taurus2 1.60 2 25%
Rattus norvegicus2 2.05 0 24%
synthetic construct2 2.05 2 24%
Caenorhabditis elegans1 2.39 1 24%
Spodoptera frugiperda1 2.59 1 24%

Seed sequence

1154 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

1MQYLNIKEDC NAMAFCAKMR SSKKTEVNLE APEPGVEVIF YLSDREPLRL GSGEYTAEEL
61CIRAAQACRI SPLCHNLFAL YDENTKLWYA PNRTITVDDK MSLRLHYRMR FYFTNWHGTN
121DNEQSVWRHS PKKQKNGYEK KKIPDATPLL DASSLEYLFA QGQYDLVKCL APIRDPKTEQ
181DGHDIENECL GMAVLAISHY AMMKKMQLPE LPKDISYKRY IPETLNKSIR QRNLLTRMRI
241NNVFKDFLKE FNNKTICDSS VSTHDLKVKY LATLETLTKH YGAEIFETSM LLISSENEMN
301WFHSNDGGNV LYYEVMVTGN LGIQWRHKPN VVSVEKEKNK LKRKKLENKH KKDEEKNKIR
361EEWNNFSYFP EITHIVIKES VVSINKQDNK KMELKLSSHE EALSFVSLVD GYFRLTADAH
421HYLCTDVAPP LIVHNIQNGC HGPICTEYAI NKLRQEGSEE GMYVLRWSCT DFDNILMTVT
481CFEKSEQVQG AQKQFKNFQI EVQKGRYSLH GSDRSFPSLG DLMSHLKKQI LRTDNISFML
541KRCCQPKPRE ISNLLVATKK AQEWQPVYPM SQLSFDRILK KDLVQGEHLG RGTRTHIYSG
601TLMDYKDDEG TSEEKKIKVI LKVLDPSHRD ISLAFFEAAS MMRQVSHKHI VYLYGVCVRD
661VENIMVEEFV EGGPLDLFMH RKSDVLTTPW KFKVAKQLAS ALSYLEDKDL VHGNVCTKNL
721LLAREGIDSE CGPFIKLSDP GIPITVLSRQ ECIERIPWIA PECVEDSKNL SVAADKWSFG
781TTLWEICYNG EIPLKDKTLI EKERFYESRC RPVTPSCKEL ADLMTRCMNY DPNQRPFFRA
841IMRDINKLEE QNPDIVSEKK PATEVDPTHF EKRFLKRIRD LGEGHFGKVE LCRYDPEGDN
901TGEQVAVKSL KPESGGNHIA DLKKEIEILR NLYHENIVKY KGICTEDGGN GIKLIMEFLP
961SGSLKEYLPK NKNKINLKQQ LKYAVQICKG MDYLGSRQYV HRDLAARNVL VESEHQVKIG
1021DFGLTKAIET DKEYYTVKDD RDSPVFWYAP ECLMQSKFYI ASDVWSFGVT LHELLTYCDS
1081DSSPMALFLK MIGPTHGQMT VTRLVNTLKE GKRLPCPPNC PDEVYQLMRK CWEFQPSNRT
1141SFQNLIEGFE ALLK

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 Structural insights into multitargeting Mycobacterium tuberculosis Pkn kinases. Microbiol Spectr doi:10.1128/spectrum.00049-26
2026 Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors. Cancer Discov doi:10.1158/2159-8290.CD-26-0251
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 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 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 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 Discovery of LAS194046: A Potent and Selective pan-Janus Kinase (JAK) Inhibitor with a Suitable Profile for Inhaled Administration. J.Med.Chem. doi:10.1021/acs.jmedchem.6c00169
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 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 A twist in the tale: shifting from covalent targeting of a tyrosine in JAK3 to a lysine in MK2. Rsc Med Chem doi:10.1039/d5md00440c
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
2025 A model for decoding resistance in precision oncology: acquired resistance to FGFR inhibitors in cholangiocarcinoma. Ann Oncol doi:10.1016/j.annonc.2024.12.011
2025 Optimization of Aminoindazole derivatives as highly selective covalent inhibitors for wild-type and mutant FGFR4. Bioorg.Chem. doi:10.1016/j.bioorg.2025.108469
2025 Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST. J.Med.Chem. doi:10.1021/acs.jmedchem.4c02472