8W0Q

Pembrolizumab CDR-H3 Loop Mimic

Summary for 8W0Q

• Entry DOI: 10.2210/pdb8w0q/pdb
• NMR Information: BMRB: 31146
• Descriptor: Pembrolizumab CDR-H3 Loop Mimic (1 entity in total)
• Functional Keywords: cdr-h3 loop, antibody, bulged hairpin, conformational ensemble, beta-hairpin, peptide mimic, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 2667.96

Authors

Feig, M.,Roche, S.P. (deposition date: 2024-02-14, release date: 2024-07-03, Last modification date: 2024-07-31)

Primary citation

Zhao, G.,Richaud, A.D.,Williamson, R.T.,Feig, M.,Roche, S.P.
De Novo Synthesis and Structural Elucidation of CDR-H3 Loop Mimics.
Acs Chem.Biol., 19:1583-1592, 2024

PubMed Abstract: The binding affinity of antibodies to specific antigens stems from a remarkably broad repertoire of hypervariable loops known as complementarity-determining regions (CDRs). While recognizing the pivotal role of the heavy-chain 3 CDRs (CDR-H3s) in maximizing antibody-antigen affinity and specificity, the key structural determinants responsible for their adaptability to diverse loop sequences, lengths, and noncanonical structures are hitherto unknown. To address this question, we achieved a de novo synthesis of bulged CDR-H3 mimics excised from their full antibody context. CD and NMR data revealed that these stable standalone β-hairpin scaffolds are well-folded and retain many of the native bulge CDR-H3 features in water. In particular, the tryptophan residue, highly conserved across CDR-H3 sequences, was found to extend the kinked base of these β-bulges through a combination of stabilizing intramolecular hydrogen bond and CH/π interaction. The structural ensemble consistent with our NMR observations exposed the dynamic nature of residues at the base of the loop, suggesting that β-bulges act as molecular hinges connecting the rigid stem to the more flexible loops of CDR-H3s. We anticipate that this deeper structural understanding of CDR-H3s will lay the foundation to inform the design of antibody drugs broadly and engineer novel CDR-H3 peptide scaffolds as therapeutics.

PubMed: 38916527
DOI: 10.1021/acschembio.4c00236

Experimental method

SOLUTION NMR