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Related Structure Help

3D structure can often provide detailed information on a protein's biological function and mechanism of action. While 3D structure has been determined experimentally for only a small fraction of known proteins, some structure information may be inferred by comparison to related structures from the same sequence family. The related structure information service is intended to provide access to this information. It presents a 3-D view of the related structure, together with an alignment display mapping conserved residues from the target protein onto the related structure. Analysis of this kind may help user identify residues critical for DNA binding, for example, or obtain information on interactions between an enzyme and its substrates or inhibitors.


What is expected from the "Related Structure Service"?

This service detects related structures by sequence similarity analysis and allows the user to visualize sequence-structure alignments with Entrez's 3D viewer Cn3D. It provides two pages: a related structure summary page and an alignment visualization page. On the related structure summary page, it lists all the related structures currently available, and shows the footprints of the alignment between the sequence of interest and each of its homologous neighbors in a graphic display. The list can be sorted with various sequence similarity measure, and can be shortened by choosing a lower redundancy level for the related structure list. In addition, it shows conserved domains of the query protein sequence. A list of descriptions for the related structures are also given in a text table. On the alignment visualization page, the service allows the user to visualize the alignment between the query protein sequence and homologous sequences, and along with a 3-D graphic view of the homolog's structure.

What does the graphic display on the related structure summary page tell you?

On the summary page displayed in graphic format, the light grey bar following "Query" is a ruler representing the query sequence. The bars following "CDs", if present, indicate the conserved domains that the query protein contains. The pink bars below "Structure" show footprints of the alignments between the query protein and its related structures, i.e. the regions of the query protein that may be aligned with a protein with known structure. Such regions are displayed as red on the query sequence.

How can one access the alignment and alignment visualization tool?

On the summary page displayed in graphic format, those pink bars below "Structure" represent footprints of the alignment. Click on these bars will launch the alignment display (visualization page).

How can one interpret the alignment display?

On the alignment visualization page, residues which are aligned are shown in upper case letters, among which identical ones are colored in red, the rest in blue. Unaligned residues are displayed in lower case letters and colored in grey.

What tool is needed to visualize the alignment and related protein structure together?

Entrez's 3D viewer Cn3D provides 3D visualization. This viewer must be installed on the user's computer and set up as a helper application for the user's web browser in order to view the 3-dimensional protein structure. Please visit the Cn3D tutorial for more description of this viewer.

How does one launch Cn3D viewer for visualization?

On the alignment visualization page, set the selection as "View in Cn3d", then click on "Get 3D Structure data" to launch Cn3D. Please note that the Cn3D viewer must be installed on the user's computer, and set up as a helper application for the user's web browser in order to view the 3-dimensional protein structure.

Tips on using Cn3D viewer

Cn3D has many features a user may want to master. The top one might be its highlighting function. Residues highighted in the structure window will be automatically highlighted in the sequence window, and vice versa if structure data for the residues is present. Thus Cn3D's highlighting tools allow mapping of conserved residues onto the 3D structure. In the example shown below, several residues around the P-loop in the AAA Atpase p97 are highlighted in yellow in the sequence window, and similarly highlighted in structure window. One can identify the residues involved in interactions between the ATPase domain and the bound ADP.

Can one save the alignment along with the structure data into a file?

Yes. On the alignment visualization page, set the selection as "Save to File", then click on "Get 3D Structure data" to save an ASN file. One can view this file later using Cn3D.

How to access the "Related Structure Service"

Currently, the NCBI Blast server links to this service if related structures are detected during a blast search. On the Blast result report page, click on "Related Structures" on the top area to view a complete list of related structures. Click on in the following area on that page to view a list of related structures with identical protein sequences or a particular related structure. This service will be available for every protein in Entrez's protein sequence database in the near future.

Tips on using this service from Blast search

The Blast search page limits the number of hits and ailgnments. Some related structures may not be reported due to this limitation. Criteria settingon the Blast server on hit selection may suppress hits of related structures too. Setting the "Number of Descriptions/Alignments" from the Blast search page to a higher value or setting the search database as "pdb" may identify additional related structures.

Where does the structure data come from?

From MMDB-Entrez's structure database. MMDB is NCBI Molecular Modelling Database. It contains experimentally determined biopolymer structures obtained from the Protein Data Bank (PDB) . It provides a convenient way for biologists to get access to the wealth of information on the biological function, mechanisms of action and the evolutionary history of proteins as well as relationships between proteins. It also provides tools for structural visualization and links between other databases both in and outside NCBI.

How are non-redundant subsets of protein structure chains selected? And how can one use them?

Protein structure chains in MMDB are clustered into groups according to amino acid sequence similarity in pairwise comparisons. A representative chain is selected from each group to compile a non-redundant subset of MMDB, and only one representative of each group is shown if a certain subset redundancy level is specified. Within each cluster of similar protein chains, cluster members are ranked according to the apparent quality and completeness of the structure data. The one ranked in the first place is uaually selected as representative of that cluster. On the summary page of the related structures service, set redundancy level as "Non-identical" using the selection box following the "List" button and click on "List" button to show only representative structures which have different sequences among each other, for example. Other redundancy groups are selected by thresholds in Blast e-value, for example, the "Low redundency" represents the with Blast e-value < 10-7.

Does one expect to see more related structures in future and how soon?

MMDB is updated monthly as the protein structure database grows. So user may expect additional related structures to appear regularly.

Does the "Related Structures Service" access all the structures available?

All the structure data currently available in MMDB are searched and all relationships detected between their sequences and that of the query are shown. Some of these "related structures" could have identical sequences. Please bear it in mind that due to the settings for a Blast search and the report limitation from the Blast server, a related structure the user expects may not show up. To work around this limitation, please refer to the "tips" on accessing the "Related Structure Service" from the Blast server.

Why one may want to access alternative structures with identical sequences?

The structure for one protein may be crystallized with or without its substrates present, depending on the experimental condition and the purpose of the study. By visualizing and comparing the different states of the structure, one may infer interaction information and may observe conformations change upon substrate binding, for example.

What is a "Conserved Domain(CD)"?

Conserved domains refer to recurring units(sequence and structure motifs) in molecular evolution whose extents can be determined by comparative analysis. Molecular evolution readily uses such domains as building blocks which may be recombined in different arrangements to modulate protein function. The NCBI's Conserved Domain Database(CDD) provides detailed information for each conserved domain.

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