Ligand fitting with CCP4.
Crystal structures of protein-ligand complexes are often used to infer biology and inform structure-based drug discovery. Hence, it is important to build accurate, reliable models of ligands that give confidence in the interpretation of the respective protein-ligand complex. This paper discusses key stages in the ligand-fitting process, including ligand binding-site identification, ligand description and conformer generation, ligand fitting, refinement and subsequent validation. The CCP4 suite contains a number of software tools that facilitate this task: AceDRG for the creation of ligand descriptions and conformers, Lidia and JLigand for two-dimensional and three-dimensional ligand editing and visual analysis, Coot for density interpretation, ligand fitting, analysis and validation, and REFMAC5 for macromolecular refinement. In addition to recent advancements in automatic carbohydrate building in Coot (LO/Carb) and ligand-validation tools (FLEV), the release of the CCP4i2 GUI provides an integrated solution that streamlines the ligand-fitting workflow, seamlessly passing results from one program to the next. The ligand-fitting process is illustrated using instructive practical examples, including problematic cases such as post-translational modifications, highlighting the need for careful analysis and rigorous validation.
Structural Studies, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, England.
Robert A
RA
Nicholls
D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004583:Electrons; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D012984:Software; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000737:chemistry / Q000378:metabolism
D008024:Ligands; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011506:Proteins; D054852:Small Molecule Libraries; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; C483041:PARP2 protein, human; D011065:Poly(ADP-ribose) Polymerases
CCP4; Coot; ligand fitting; model building