title: Receptor-bound conformation of cilengitide better represented by its solution-state structure than the solid-state structure.
abstract: The X-ray crystal and NMR spectroscopic structures of the peptide drug candidate Cilengitide (cyclo(RGDf(NMe)Val)) in various solvents are obtained and compared in addition to the integrin receptor bound conformation. The NMR-based solution structures exhibit conformations closely resembling the X-ray structure of Cilengitide bound to the head group of integrin αvβ3. In contrast, the structure of pure Cilengitide recrystallized from methanol reveals a different conformation controlled by the lattice forces of the crystal packing. Molecular modeling studies of the various ligand structures docked to the αvβ3 integrin revealed that utilization of the solid-state conformation of Cilengitide leads-unlike the solution-based structures-to a mismatch of the ligand-receptor interactions compared with the experimentally determined structure of the protein-ligand complex. Such discrepancies between solution and crystal conformations of ligands can be misleading during the structure-based lead optimization process and should thus be taken carefully into account in ligand orientated drug design.
authors.affiliation: Institute for Advanced Study (IAS) and Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching (Germany).
authors.forename: Udaya Kiran
authors.initials: UK
authors.lastname: Marelli
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Frank
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wahl
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Eberhardt
authors.initials: E
authors.lastname: Herdtweck
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D039302:Integrin alphaVbeta3 / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D012910:Snake Venoms / Q000737:chemistry*; D012996:Solutions
chemical_list: D039302:Integrin alphaVbeta3; D012910:Snake Venoms; D012996:Solutions; C422910:Cilengitide
keywords: Cilengitide; NMR spectroscopy; X-ray crystallography; conformational analysis; peptides