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SubstanceProtein — Protein structure

Describes the chemistry of a pharmaceutical protein: primary sequence, subunits, disulfide bridges, N/C termini, post-translational modifications. Used for insulins, monoclonal antibodies, fusion proteins, clotting factors.

Purpose of the resource

Biologics now account for 40% of drugs in development and the blockbusters of the industry (Humira, Keytruda, Stelara). For such a substance to be unambiguously identified by regulatory agencies, its amino acid sequence and disulfide bridge structure must be described precisely. SubstanceProtein is the dedicated formal structure.

A protein can have several subunits (two chains for insulin, four for an IgG: two heavy chains and two light chains), post-translational modifications (glycosylation, pegylation, lipidation, methylation, phosphorylation), modified ends (N-terminal acetylation, C-terminal amidation).

Key fields

FieldTypeCardinalityRole
sequenceTypeCodeableConcept0..1Sequence type: linear, cyclic, branched.
numberOfSubunitsinteger0..1Number of subunits (1 for a peptide, 2 for insulin, 4 for IgG…).
disulfideLinkagestring[]0..*List of disulfide bridges (format subunit-position : subunit-position).
subunitBackboneElement[]0..*Description of each subunit.
subunit.subunitinteger0..1Subunit index.
subunit.sequencestring0..1Primary sequence in one-letter IUPAC code (G, I, V, E…).
subunit.lengthinteger0..1Length (amino acids).
subunit.sequenceAttachmentAttachment0..1Sequence externalised (FASTA, PDB…).
subunit.nTerminalModificationIdIdentifier0..1Identifier of the N-terminal modification.
subunit.nTerminalModificationstring0..1N-terminal modification narrative (acetyl, formyl, free…).
subunit.cTerminalModificationIdIdentifier0..1Identifier of the C-terminal modification.
subunit.cTerminalModificationstring0..1C-terminal modification (amide, methyl ester, free…).

JSON example

Human insulin: chain A (21 aa) and chain B (30 aa) connected by 3 disulfide bridges (A6-A11 intra-A, A7-B7, A20-B19 inter-chain):

json substanceprotein-example.json 
{
  "resourceType": "SubstanceProtein",
  "id": "example-insulin",
  "sequenceType": {
    "coding": [{
      "system": "http://terminology.hl7.org/CodeSystem/protein-sequence-type",
      "code": "linear",
      "display": "Linear sequence"
    }]
  },
  "numberOfSubunits": 2,
  "disulfideLinkage": [
    "1-A6:A11",
    "1-A7:B7",
    "1-A20:B19"
  ],
  "subunit": [{
    "subunit": 1,
    "sequence": "GIVEQCCTSICSLYQLENYCN",
    "length": 21,
    "sequenceAttachment": {
      "contentType": "text/plain",
      "title": "Insulin chain A"
    },
    "nTerminalModificationId": {
      "system": "http://terminology.hl7.org/CodeSystem/n-terminal-mod",
      "value": "Glycine"
    },
    "nTerminalModification": "Free amino group",
    "cTerminalModificationId": {
      "system": "http://terminology.hl7.org/CodeSystem/c-terminal-mod",
      "value": "Asparagine"
    },
    "cTerminalModification": "Free carboxylic group"
  }, {
    "subunit": 2,
    "sequence": "FVNQHLCGSHLVEALYLVCGERGFFYTPKT",
    "length": 30,
    "sequenceAttachment": {
      "contentType": "text/plain",
      "title": "Insulin chain B"
    }
  }]
}

Typical use cases

  • Monoclonal antibodies: IgG1, IgG2, IgG4 — heavy + light chains + isotype.
  • Insulins: human insulin, rapid analogues (Aspart, Lispro), long-acting (Glargine, Detemir).
  • Recombinant hormones: hGH, erythropoietin, FSH, GnRH agonists.
  • Therapeutic enzymes: replacement therapies for lysosomal disorders (alglucosidase, idursulfase…).
  • Fusion proteins: etanercept (TNFR2-Fc), abatacept (CTLA4-Ig), aflibercept (VEGF-trap).

Common pitfalls

  • Non-standard disulfide notation: disulfideLinkage must follow subunit-position : subunit-position. Any other notation breaks validators.
  • Glycosylation forgotten: the N-297 glycoform of an antibody is crucial for biosimilarity. SubstanceProtein does not carry glycoforms: use SubstanceDefinition + extensions or an attachment describing the glycoprofile.
  • Isotype confusion: IgG1, IgG2, IgG3, IgG4 have different constants. Must be declared in sequenceAttachment or the parent SubstanceDefinition.
  • Subunit = chain ≠ domain: a subunit is a distinct polypeptide chain. Not to be confused with domains (Fab, Fc, CDR…) of the same chain.
  • N/C-ter modifications without coding: prefer a coded identifier (ChEBI, UNII) over free text.
  • SubstanceDefinition — references this block via structure.
  • SubstanceNucleicAcid, SubstancePolymer, SubstanceReferenceInformation, SubstanceSourceMaterial.
  • MedicinalProductDefinition — marketing authorisation.
  • Ingredient — active substance of a protein drug.

See also: SubstanceDefinition and Ingredient.