Extended Data Fig. 4: Carboxylate-containing S2-binding moieties induce K118 side-chain and S123 backbone migration.
From: Discovery and molecular basis of subtype-selective cyclophilin inhibitors
a, Superposition of co-crystal structures of CypD with B2 (gray) and B23 (green). The side-chain of K118 typically is oriented away from the S2 pocket, as shown in co-crystal structures that do not contain carboxylate ligands, such as that of B2. A properly placed carboxylate group (B23) migrates K118’s side-chain into the S2 pocket (red arrow), forming a salt bridge along with a hydrogen bond with S119’s peptide backbone (black dashes). Also shown is the S123 loop migration that occurs when carboxylate-containing biphenyl groups bind deep into the S2 pocket (black arrow). b, Co-crystal structure superposition of CypD with B23 (green), B25 (pink), B52 (red) and B53 (purple). All properly placed carboxylate-containing ligands induce the same K118 and S123 conformational change. Dicarboxylates such as B52 and B53 also present the second carboxylate towards the S123 gatekeeper residue, the former exhibiting a hydrogen bond (black dashes) with the S123–R124 peptide backbone.
