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PDBsum entry 5iv2
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Immune system
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PDB id
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5iv2
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Contents |
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213 a.a.
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216 a.a.
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12 a.a.
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PDB id:
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Immune system
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Title:
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Cetuximab fab in complex with arg9cir meditope variant
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Structure:
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Cetuximab fab, light chain. Chain: a, c. Engineered: yes. Cetuximab fab, heavy chain. Chain: b, d. Engineered: yes. Meditope variant. Chain: e, f. Engineered: yes
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Source:
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Mus musculus, homo sapiens. Mouse, human. Organism_taxid: 10090, 9606. Expressed in: unidentified. Expression_system_taxid: 32644. Synthetic: yes. Synthetic construct. Organism_taxid: 32630
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Resolution:
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2.48Å
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R-factor:
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0.167
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R-free:
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0.211
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Authors:
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K.P.Bzymek,J.C.Williams
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Key ref:
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K.P.Bzymek
et al.
(2016).
Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope-Fab complexes.
Acta Crystallogr F Struct Biol Commun,
72,
820-830.
PubMed id:
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Date:
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18-Mar-16
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Release date:
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26-Oct-16
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PROCHECK
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Headers
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References
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No UniProt id for this chain
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Acta Crystallogr F Struct Biol Commun
72:820-830
(2016)
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PubMed id:
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Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope-Fab complexes.
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K.P.Bzymek,
K.A.Avery,
Y.Ma,
D.A.Horne,
J.C.Williams.
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ABSTRACT
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Herein, multiple crystal structures of meditope peptide derivatives
incorporating natural and unnatural amino acids bound to the cetuximab Fab
domain are presented. The affinity of each derivative was determined by surface
plasmon resonance and correlated to the atomic structure. Overall, it was
observed that the hydrophobic residues in the meditope peptide, Phe3, Leu5 and
Leu10, could accommodate a number of moderate substitutions, but these
invariably reduced the overall affinity and half-life of the interaction. In one
case, the substitution of Phe3 by histidine led to a change in the rotamer
conformation, in which the imidazole ring flipped to a solvent-exposed position.
Based on this observation, Phe3 was substituted by diphenylalanine and it was
found that the phenyl rings in this variant mimic the superposition of the Phe3
and His3 structures, producing a moderate increase, of 1.4-fold, in the
half-life of the complex. In addition, it was observed that substitution of Leu5
by tyrosine and glutamate strongly reduced the affinity, whereas the
substitution of Leu5 by diphenylalanine moderately reduced the half-life (by
approximately fivefold). Finally, it was observed that substitution of Arg8 and
Arg9 by citrulline dramatically reduced the overall affinity, presumably owing
to lost electrostatic interactions. Taken together, these studies provide
insight into the meditope-cetuximab interaction at the atomic level.
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Links
