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IntroductionThe positioning of the DFG motif in the activation loop of a protein kinase has an effect on the size and properties of the ATP binding pocket. Most kinase inhibitors target the kinase with the DFG inwards to the ATP binding site. Type-II inhibitors target the site where the DFG motif is in the out position which opens up the pocket and provides additional hydrophobic binding sites. Targeting DFG-out conformations can improve inhibitor specificity and slower-off rates.
TutorialIn this example we will look at two kinase structures and compare their binding pockets. One of the structures is bound to the Type-II inhibitor Imatinib (Gleevec) a drug used to treat Chronic Myelogenous Leukemia. We will use ICM tools to look at the side-chains that interact with the inhibitor and compare the pocket with a DFG-in structure using ICMPocketFinder. Please click on the links provided to learn more about the methods used.
Background When inspecting a ligand binding pocket it is important to check that the true pocket is formed by chains which are not explicitely present in a PDB entry. Therefore it is necesary to use Tools/X Ray/Crystallographic Neighbor to find all molecules/subunits or chains involved in the interaction with the ligand. Molecular objects and 3D density maps may contain information about crystallographic symmetry. It consists of the following parameters:
Example As an example let us look at Cycloldextrin glycosyltransferase (PDB Code: 1CDG). The problem with docking to this receptor is that the true pocket is formed by chains which are not explicitly present in the PDB entry. Site mb1 includes serine 382. This cannot be predicted just by looking at the structure. Therefore we need to identify symmetry related molecules to this protein.
Background When preparing a PDB for analysis (eg docking or modeling) it is important to check the reported occupancies and b-factors. The occupancy is a fraction of atimic density at a given center. If there are two eqally occupied conformers both will have an occupancy of 0.5 - the normal value is 1 range 0-1. The *{B-Factor} is the mean-square displacement of atom from its position in the model - the normal range is 5-50. One way of visualizing the occupancy and b-factor is by coloring the structure by these values. You can do this by clicking and holding on a representation button in the display panel and selecting Color-by. As an example let us look at the crystal structure 1ATP
For some very high resolution structures two alternative conformations for a residue are provided. Therefore for docking you need to decide to use one conformation of the residue or generate seveal separate docking models. This could be performed using multiple receptor conformation docking. Here is an example of alternative residue orientations found in a crystal structure of a Fatty Acid Binding protein in complex with stearic acid.
Objective Here we will investigate the biological environment of a virus protein . PDB code 1DWN. Background It is very useful to know how a protein from the PDB may look in a biological environment. The PDB entries solved by X-ray crystallography and deposited in the PDB contain the information about the crystal structure rather than the biologically relevant structure. For example, for a viral capsid only one instance of capsid protein complex will be deposited and only one or two molecules of haemoglobin that is a tetramer in solution maybe deposited. In some other cases the asymmetric unit may contain more than one copy of a biologically monomeric protein. ICM reads the biological unit information and has a tool to generate a biological unit. Not every PDB entry has the biological unit information. Instructions
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