6azl

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Structure of cetuximab with aminoheptanoic acid-linked N-carboxyethylarginine meditope variant

Structural highlights

6azl is a 6 chain structure with sequence from Homo sapiens, Mus musculus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.482Å
Ligands:011, C67, SO4
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IGKC_HUMAN Defects in IGKC are the cause of immunoglobulin kappa light chain deficiency (IGKCD) [MIM:614102. IGKCD is a disease characterized by the complete absence of immunoglobulin kappa chains.[1]

Function

IGKC_HUMAN

Publication Abstract from PubMed

Meditope, a cyclic 12-residue peptide, binds to a unique binding side between the light and heavy chains of the cetuximab Fab. In an effort to improve the affinity of the interaction, it was sought to extend the side chain of Arg8 in the meditope, a residue that is accessible from the other side of the meditope binding site, in order to increase the number of interactions. These modifications included an n-butyl and n-octyl extension as well as hydroxyl, amine and carboxyl substitutions. The atomic structures of the complexes and the binding kinetics for each modified meditope indicated that each extension threaded through the Fab `hole' and that the carboxyethylarginine substitution makes a favorable interaction with the Fab, increasing the half-life of the complex by threefold compared with the unmodified meditope. Taken together, these studies provide a basis for the design of additional modifications to enhance the overall affinity of this unique interaction.

Meditope-Fab interaction: threading the hole.,Bzymek KP, Ma Y, Avery KN, Horne DA, Williams JC Acta Crystallogr F Struct Biol Commun. 2017 Dec 1;73(Pt 12):688-694. doi:, 10.1107/S2053230X17016272. Epub 2017 Nov 18. PMID:29199990[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
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Template-Catalyzed, Disulfide Conjugation of Monoclonal Antibodies Using a Natural Amino Acid Tag.
King et al. (2018)
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References

  1. ↑ Stavnezer-Nordgren J, Kekish O, Zegers BJ. Molecular defects in a human immunoglobulin kappa chain deficiency. Science. 1985 Oct 25;230(4724):458-61. PMID:3931219
  2. ↑ Bzymek KP, Ma Y, Avery KN, Horne DA, Williams JC. Meditope-Fab interaction: threading the hole. Acta Crystallogr F Struct Biol Commun. 2017 Dec 1;73(Pt 12):688-694. doi:, 10.1107/S2053230X17016272. Epub 2017 Nov 18. PMID:29199990 doi:http://dx.doi.org/10.1107/S2053230X17016272

Contents


PDB ID 6azl

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