Structures

Structure browser

The structure table shows an annotated list of published GPCR structures. The table can be sorted by each column by clicking on the header. The search fields below each header can be used to filter the structures, e.g. show only those with a co-crystallized agonist or X-ray resolution < 2.5 Å.

To view an alignment of the selected structure sequences, click the “Align” button. Downloading multiple structures at the same time is available with the “Download” button. The “Show representative” button will filter the table by only showing structures that are the representative structures for the given receptor in each state. These structures are the ones which have the most GPCRdb generic numbered positions present in the structure and have high resolution.

Refined structures

GPCRdb provides regularly updated refined structures where missing segments are modeled using the GPCRdb homology modeling pipeline (Pándy-Szekeres et al. 2018). This entails modeling missing segments (helix ends, loops, H8), reverting mutations to wild type and remodeling distorted regions based on our in-house manual structure curation. The refined structures are available on the Structures (gpcrdb.org/structure) and Structure models pages (gpcrdb.org/structure/homology_models).

Structure statistics

The statistics page shows a bar graph with the number of structures available by year (and grouped by the endogenous ligand type of the receptors), a bar graph showing the resolution ranges of the available structures, and phylogenetic trees for each receptor class, with receptors with determined structures highlighted.

The graphs are automatically updated when new data is added to GPCRdb, making them ideal for use in publications and presentations.

Structure models

With every database update GPCRdb builds a homology model repository containing models for every human GPCR in three different activation states (inactive, intermediate, active). Class T is based on class A and class B2 is based on class B1. The models are created based on the GPCRdb homology modeling pipeline (Pándy-Szekeres et al. 2018) that utilizes an automated chimeric modeling approach. For every model a single main template is selected and atomic coordinates from alternative local templates are swapped-in for sections of the model where either the main template is missing coordinates or the algorithm predicts a better template based on multiple criteria. These affect helix ends, loops, H8 and structural anomalies like bulges and constrictions. Furthermore, an in-house rotamer library is applied for side-chains where there is a mismatch between the modeled receptor and the template. The newest version of the homology models can be found on the Structure models page (gpcrdb.org/structure/homology_models) where users can download the older versions as well from the Archive.

Structure model statistics

To assess GPCRdb homology models we provide root-mean-square deviation (RMSD) calculations between the first published experimental structure of a receptor and the latest GPCRdb model before that publish date. The model is in the same activation state as the experimental structure. After a structure is released, manually annotated structural data is added to GPCRdb with the next release. In some cases, there is a delay between the manual annotation and the release of the structure; therefore, some model versions can have a later date than the publication date of the modeled structure; however, these do not contain any information from the modeled structure.

For such structural comparisons the superpositioning method is key. The GPCRdb RMSD calculation workflow employs a sequence-dependent comparison where atoms that are missing from either the structure or the model are excluded and only the 7-transmembrane (7TM) backbone atoms (N, CA, C) determined by GPCRdb sequence alignments are used for the superpositioning. All RMSD calculations, which are also sequence-dependent, are carried out from this superpositioned state. For loop segment RMSD scores this makes it possible to factor in not only the structural characteristics of the loop but also its position relative to the 7TM bundle. Futhermore, different properties of the models can be assessed based on which atoms we select for the RMSD calculations. The RMSD calculations themselves were done with the following python code:

round(np.sqrt(sum(sum((array1[1:]-array2[1:])**2))/array1[1:].shape[0]),1)

where array1 and array2 are numpy arrays with atomic coordinates from structure and model respectively.

RMSD categories currently available for GPCRdb models:

  • Overall all: all atoms
  • Overall backbone: all backbone atoms
  • 7TM all: all atoms of 7TM residues
  • 7TM backbone: backbone atoms of 7TM residues
  • H8: Helix 8 backbone atoms
  • ICL1: Intracellular loop 1 backbone atoms
  • ECL1: Extracellular loop 1 backbone atoms
  • ICL2: Intracellular loop 2 backbone atoms
  • ECL2: Extracellular loop 2 backbone atoms
  • ECL3: Extracellular loop 3 backbone atoms

Parts of these results were published in Kooistra et al. 2020; however some values in the table online differ from values published in the paper due to the inclusion of RosettaGPCR models in the latter case. The differences arise from some missing atoms in the added models which lead to different superpositionings and different atoms included for RMSD calculations.

Structure superposition

The superposition tool allows users to upload two or more structures (or models) and superpose them based on a user-specified segment selection. Using the tool is a two step process.

  1. Select structures to upload. Only on reference structure can be uploaded, but multiple structures to superpose on the reference can be uploaded. To select many structures for upload, hold down the Control key (or Command on Mac) while selecting
  2. After structures have been uploaded, the user is presented with a sequence segment selection page. The user can select one or more sequence segments, and/or expand each segment to select the residues within it individually. Residues selected individually are grouped into a custom sequence segment.

Generic residue numbering (PDB)

The PDB file residue numbering tool adds generic residue numbers from GPCRdb to any GPCR structure or model. This can be useful when comparing structures visually.

A user simply uploads her structure and downloads a modified version of that structure, where b factors of certain atoms have been replaced with generic numbers. Note that CA atoms will be assigned a number in GPCRdb notation, and N atoms will be annotated with Ballesteros-Weinstein scheme.

On the structure download page, users can download scripts to visualize the generic numbers in PyMOL and Maestro.