Kinase Conservation Analysis Panel

Annotate ligand binding residues for a kinase holostructure and calculate a position specific conservation score for each residue.

To display this panel, do one of the following:
  • click the Tasks button and browse to Structure Analysis → Kinase Conservation Analysis
  • Using
  • Features

Using the Kinase Conservation Analysis Panel

One of the key pieces of information in drug selectivity optimization is binding site similarities across off-target landscapes. The kinase conservation analysis method is designed to provide sequence conservation information for small molecule binding site residues of a query kinase sequence in human kinome spaces. Such binding site conservation information of the target kinase against human kinome would provide clues for the potential off-targets which should be considered in the early stage of the selectivity optimization process. The method is fast and covers ~500 human kinases, including the ones that are known to be pharmacologically important but still often missing from experimental assays.

The Kinase Conservation Analysis Panel requires a holo structure of a kinase bound with a drug-like small molecule as input. It is important to build the input structure with all the missing loops, residues and atoms. We also recommend that the non-kinase domains are removed. A warning is displayed if the input structure is not a receptor-ligand complex.

Distance and angle cutoffs are used to identify binding site residues. Conservation information is then calculated for each residue, and displayed in the panel along with a pie chart of residue frequency in other kinases.

For information on command line usage and options, see kinase_conservation_analysis.py Command Help.

Kinase Conservation Analysis Panel Features

Get complex from option menu

Choose the structure source for the analysis.

  • Project Table (n selected entries)—Use the entries that are currently selected in the Project Table or Entry List. The number of entries selected is shown on the menu item. An icon is displayed to the right which you can click to open the Project Table and select entries. When this option is selected, a Load button is displayed to the right.
  • Workspace (included entry)—Use the entry that is currently included in the Workspace. Only one entry must be included in the Workspace. When this option is selected, a Load button is displayed to the right.
  • File—Use the specified file. When this option is selected, the File name text box and Browse button are displayed.
Browse button

Click Browse and navigate to the desired files. The allowed file types are: Maestro files (.bld, .cms, .cmsgz, .mae, .mae,gz, .maegz).

Load button

Load the complex from the Project Table or Workspace into the panel.

Receptor Chain option menu and Pick option

Choose which receptor chain on the kinase holostructure should be used for the analysis.

Ligand option menu and Pick option

The ligand option menu is automatically populated. Choose a ligand from the menu and select the Pick option to choose it.

Distance text box

Choose the cutoff distance for identifying the binding site residues, in angstroms. Residues on the selected receptor chain within the cutoff distance from the selected ligand are included.

Angle text box

Choose a side chain angle cutoff to determine if a residue is pointing to the ligand. in degrees. Only values from 0 to 180 degrees are allowed.

Apply button

Click the button to populate the Residue table using the Distance and Angle cutoffs. If you do not see your residues of interest in the Residue table, you can adjust the cutoffs and click Apply to repopulate the table. Results are saved in a kinase_conservation_n directory where n is incremented with each run.

Residue table

Lists the residues that fall within the set cutoffs. Select a row to visualize its frequency in the Residue Frequencies plot to the right. The Maestro Workspace focuses on the selected residue. You can click on a column header to sort the table by that column. The columns of the Residue table are as follows:

  • Residue—The 1-letter residue name.

  • Residue ID—The receptor chain and residue number.

  • Conservation Category—Each ligand-binding residue in the query kinase structure is assigned a conservation category. These categories—Very Low, Low, Medium, High, and Very High—are determined empirically based on z-scores and p-values derived from the conservation score distribution of approximately 130,000 residues across ~500 human kinases. A "Very Low" conservation score indicates that the residue is not conserved and is significantly rare (z-score < -1 and p-value < 0.005) at that position within the human kinome. Conversely, a "Very High" score indicates that the residue is highly conserved across the human kinome. One important application of conservation categories is in identifying residues that are rare with "Very Low" conservation category; these residues, due to their rarity within the kinome, represent high-priority target selectivity handle residues for small molecule development during kinase target selectivity optimization.

Save as image button

Save the Residue Frequencies plot as an image, in PNG or JPEG format. Opens a file selector, so you can navigate to a location and name the file.

Save as CSV button

Save the Residue table along with the residue frequency percentages as a CSV. Opens a file selector, so you can navigate to a location and name the file.

Residue Frequencies plot

The residue frequency, i.e, the number of occurrences in other kinases, is presented as a pie chart. Click a residue in the legend to highlight the slice in the pie chart. You can hover over a slice directly to show a tooltip with the number of kinases and the percentage. Click on the slice to show a tooltip with a list of kinases sorted by conservation score. You can save the list as a .txt file by clicking the Save list link.

Status bar

The status bar displays information about the current job settings and status for the panel. The settings includes the job name, task name and task settings (if any), number of subjobs (if any) and the host name and job incorporation setting. The job status can include messages about job start, job completion and incorporation.

Use the Reset button to reset the panel to its default settings and clear any data from the panel. You can also reset the panel from the Job toolbar.

The status bar also contains the Help button , which opens the help topic for the panel in your browser. If the panel is used by one or more tutorials, hovering over the Help button displays a button, which you can click to display a list of tutorials (or you can right-click the Help button instead). Choosing a tutorial opens the tutorial topic.