Summary: TspO/MBR family
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Translocator protein Edit Wikipedia article
|, BPBS, BZRP, DBI, IBP, MBR, PBR, PBS, PKBS, PTBR, mDRC, pk18, translocator protein|
Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. In humans, the translocator protein is encoded by the TSPO gene. It belongs to family of tryptophan-rich sensory proteins. Regarding intramitochondrial cholesterol transport, TSPO has been proposed to interact with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria, though evidence is mixed.
In animals, TSPO (PBR) is a mitochondrial protein usually located in the outer mitochondrial membrane and characterised by its ability to bind a variety of benzodiazepine-like drugs, as well as to dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway.
TSPO has many proposed functions depending on the tissue. The most studied of these include roles in the immune response, steroid synthesis and apoptosis.
Cholesterol transport and bile acid biosynthesis
Mitochondrial cholesterol transport is a molecular function closely tied to TSPO in the scientific literature. TSPO binds with high affinity to the lipid cholesterol, and pharmacological ligands of TSPO facilitate cholesterol transport across the mitochondrial intermembrane space to stimulate steroid synthesis and bile acid synthesis in relevant tissues. However, TSPO deletion in genetically engineered mouse models has yielded mixed results regarding the physiological necessity of TSPO's role in steroidogenesis. Deletion of TSPO in steroidogenic Leydig cells did not impair synthesis of the steroid testosterone. Thus, though biochemical and pharmacological experimentation suggest an important role for TSPO in cellular cholesterol transport and steroid biosynthesis, TSPO's necessity in this process remains controversial.
Regulation in the heart
TSPO (Translocator protein) acts to regulate heart rate and contractile force by its interaction with voltage-dependent calcium channels in cardiac myocytes. The interaction between TSPO and calcium channels can alter cardiac action potential durations, thus contractility of the heart. In healthy individuals, TSPO has a cardio-protective role. When TSPO is up-regulated in the presence of infections, it can limit the inflammatory response, which can be cardio-damaging.
PBRs (TSPOs) have many actions on immune cells including modulation of oxidative bursts by neutrophils and macrophages, inhibition of the proliferation of lymphoid cells and secretion of cytokines by macrophages. Expression of TSPO is also linked to inflammatory responses that occur after ischemia-reperfusion injury, following brain injury, and in some neurodegenerative diseases.
Increased expression of TSPO is linked to the inflammatory responses in the heart that may cause myocarditis, which can lead to myocardial necrosis. TSPO is present in mast cells and macrophages, indicating its role in the immune system. Oxidative stress is a strong contributing factor to cardiovascular disease, and often occurs because of inflammation caused by ischemia reperfusion injury. Coxsackievirus B3 (CVB3) causes immune cells CD11b+ (present on macrophages) to stimulate inflammatory infiltration. Functionally, CD11b+ regulates leukocyte adhesion and migration to regulate the inflammatory response. Following infection, CD11b+ is up-regulated, activating these immune responses, which then activate an increased expression of TSPO. These immune cells can cause myocarditis which can progress to dilated cardiomyopathy and heart failure.
Ligands of TSPO have been shown to induce apoptosis in human colorectal cancer cells. In lymphatic tissues, TSPO modulates apoptosis of thymocytes via reduction of mitochondrial transmembrane potential.
TSPO is found in many regions of the body including the human iris/ciliary-body. Other tissues include the heart, liver, adrenal and testis, as well as hemopoietic and lymphatic cells. "Peripheral" benzodiazepine receptors are also found in the brain, although only at around a quarter the expression levels of the "central" benzodiazepine receptors located at the plasma membrane.
Pharmacological activation of TSPO has been observed to be a potent stimulator of steroid biosynthesis  including neuroactive steroids such as allopregnanolone in the brain, which exert anxiolytic properties. Thus, TSPO ligands such as emapunil (XBD-173) or alpidem have been proposed to be useful as potential anxiolytics which may have less addiction-based side effects than traditional benzodiazepine-type drugs., though toxicity side-effects remain a significant barrier in drug development.
A 2013 study led by researchers from USC Davis School of Gerontology showed that TSPO ligands can prevent and at least partially correct abnormalities present in a mouse model of Alzheimer's disease.
TSPO as a biomarker is a newly discovered non-invasive procedure, and has also been linked as a biomarker for other cardiovascular related diseases including: myocardial infarction (due to ischemic reperfusion), cardiac hypertrophy, atherosclerosis, arrhythmias, and large vessel vasculitis. TSPO can be used as a biomarker to detect the presence and severity of inflammation in the heart and atherosclerotic plaques.Inhibiting the over-production of TSPO can lead to a reduced incidence of arrhythmias which are most often caused by ischemia reperfusion injury. TSPO ligands are used as a therapy after ischemia reperfusion injury to preserve the action potentials in cardiac tissue and restore normal electrical activity of the heart. Higher levels of TSPO are present in those with heart disease, a change that is more common in men than women because testosterone worsens the inflammation causing permanent damage to the heart.
The first high-resolution 3D solution structure of mammalian (mouse) translocator protein (TSPO) in a complex with its diagnostic PK11195 ligand was determined by means of NMR spectroscopy techniques by scientists from the Max-Planck Institute for Biophysical Chemistry in Goettingen in Germany in March 2014 (Jaremko et al., 2014) and has a PDB id: 2MGY. Obtained high-resolution clearly confirms a helical character of a protein and its complex with a diagnostic ligand in solution. The 3D structure of the mTSPO-PK11195 complex comprises five transmembrane Î±-helices (TM1 to TM5) that tightly pack together in the clockwise order TM1-TM2-TM5-TM4-TM3 (cytosol view). The mammalian TSPO in a complex with diagnostic ligand is nomomeric. The loop located in between TM1 and TM2 helices closes the entrance to the space between helices in which are bound with PK11195 molecule. Site-directed mutagenesis studies of mTSPO revealed that region important for PK11195 binding comprise amino acids from 41 to 51, because the deletion of this region resulted in the decrease in PK11195 binding (Fan et al., 2012).
Ligands of the TSPO are very useful for imaging of inflammation. For example, the radioligand [3H]PK-11195 has been used in receptor autoradiography to study neuroinflammation following brain injury. The affinity of [11C]PBR28 depends on a single polymorphism (rs6971) in the TSPO gene.
Measuring microglial activation in vivo is possible using PET imaging and radioligands binding to 18 kDa translocator protein (TSPO). Activation can be measured using the PET tracer (R)-[11C]PK11195 and others like PBR28 are under research.
- Ro5-4864 - original ligand with which TSPO receptor was characterised, now less used due to inter-species differences in binding affinity. Sedative yet also convulsant and anxiogenic in mice.
- Anthralin - 16kDa polypeptide, binds to both TSPO receptor and dihydropyridine-sensitive calcium channels with high affinity.
- Diazepam binding inhibitor (DBI) - 11kDa neuropeptide, potent agonist for TSPO receptor and stimulates steroidogenesis in vivo, also negative allosteric modulator of benzodiazepine-sensitive GABAA receptors.
- DBI 17-50 fragment - active processing product of DBI
- PK-11195 - potent and selective antagonist for both rat and human forms of TSPO.
- GRCh38: Ensembl release 89: ENSG00000100300 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000041736 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- Chang YJ, McCabe RT, Rennert H, Budarf ML, Sayegh R, Emanuel BS, Skolnick P, Strauss JF (1992). "The human "peripheral-type" benzodiazepine receptor: regional mapping of the gene and characterization of the receptor expressed from cDNA". DNA Cell Biol. 11 (6): 471â€“80. doi:10.1089/dna.1992.11.471. PMID 1326278.
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- Bogan RL, Davis TL, Niswender GD (April 2007). "Peripheral-type benzodiazepine receptor (PBR) aggregation and absence of steroidogenic acute regulatory protein (StAR)/PBR association in the mitochondrial membrane as determined by bioluminescence resonance energy transfer (BRET)". J. Steroid Biochem. Mol. Biol. 104 (1â€“2): 61â€“7. doi:10.1016/j.jsbmb.2006.10.007. PMID 17197174.
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- Morohaku K, Pelton SH, Daugherty DJ, Ronald Butler W, Deng W, Selvaraj V (2013). "Translocator Protein/Peripheral Benzodiazepine Receptor Is Not Required for Steroid Hormone Biosynthesis". Endocrinology. 155 (1): 89â€“97. doi:10.1210/en.2013-1556. PMC 3868810. PMID 24174323.
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- Chen MK, Guilarte TR (April 2008). "Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair". Pharmacology & Therapeutics. 118 (1): 1â€“17. doi:10.1016/j.pharmthera.2007.12.004. PMC 2453598. PMID 18374421.
- SantidriÃ¡n AF, Cosialls AM, Coll-Mulet L, Iglesias-Serret D, de Frias M, GonzÃ¡lez-GironÃ¨s DM, CampÃ s C, Domingo A, Pons G, Gil J (December 2007). "The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells". Haematologica. 92 (12): 1631â€“8. doi:10.3324/haematol.11194. PMID 18055986.
- Kugler W, Veenman L, Shandalov Y, Leschiner S, Spanier I, Lakomek M, Gavish M (2008). "Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glioblastoma cells exposed to erucylphosphohomocholine". Cellular Oncology. 30 (5): 435â€“50. PMC 4618834. PMID 18791274.
- Veenman L, Papadopoulos V, Gavish M (2007). "Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response". Current Pharmaceutical Design. 13 (23): 2385â€“405. doi:10.2174/138161207781368710. PMID 17692008.
- Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, Diaz G (August 2007). "Intracellular cholesterol changes induced by translocator protein (18 kDa) TSPO/PBR ligands". Neuropharmacology. 53 (2): 318â€“29. doi:10.1016/j.neuropharm.2007.05.016. PMID 17631921.
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- Da Settimo F, Simorini F, Taliani S, La Motta C, Marini AM, Salerno S, Bellandi M, Novellino E, Greco G, Cosimelli B, Da Pozzo E, Costa B, Simola N, Morelli M, Martini C (September 2008). "Anxiolytic-like effects of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis". Journal of Medicinal Chemistry. 51 (18): 5798â€“806. doi:10.1021/jm8003224. PMID 18729350.
- Taliani S, Da Settimo F, Da Pozzo E, Chelli B, Martini C (September 2009). "Translocator Protein Ligands as Promising Therapeutic Tools for Anxiety Disorders". Current Medicinal Chemistry. 16 (26): 3359â€“80. doi:10.2174/092986709789057653. PMID 19548867.
- Rupprecht R, Rammes G, Eser D, Baghai TC, SchÃ¼le C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F, Uzunov V, McAllister KH, Bertaina-Anglade V, La Rochelle CD, Tuerck D, Floesser A, Kiese B, Schumacher M, Landgraf R, Holsboer F, Kucher K (June 2009). "Translocator Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like Side Effects". Science. 325 (5939): 490â€“3. doi:10.1126/science.1175055. PMID 19541954.
- Skolnick P (November 2012). "Anxioselective anxiolytics: on a quest for the Holy Grail". Trends Pharmacol Sci. 33 (11): 611â€“620. doi:10.1016/j.tips.2012.08.003. PMC 3482271. PMID 22981367.
- Barron, A. M.; Garcia-Segura, L. M.; Caruso, D.; Jayaraman, A.; Lee, J. -W.; Melcangi, R. C.; Pike, C. J. (2013). "Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease". The Journal of Neuroscience. 33 (20): 8891â€“8897. doi:10.1523/JNEUROSCI.1350-13.2013. PMC 3733563. PMID 23678130.
- Jaremko L, Jaremko M, Giller K, Becker S, Zweckstetter M (March 2014). "Structure of the mitochondrial translocator protein in complex with a diagnostic ligand". Science. 343 (6177): 1363â€“6. doi:10.1126/science.1248725. PMC 5650047. PMID 24653034.
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TspO/MBR family Provide feedback
Tryptophan-rich sensory protein (TspO) is an integral membrane protein that acts as a negative regulator of the expression of specific photosynthesis genes in response to oxygen/light . It is involved in the efflux of porphyrin intermediates from the cell. This reduces the activity of coproporphyrinogen III oxidase, which is thought to lead to the accumulation of a putative repressor molecule that inhibits the expression of specific photosynthesis genes. Several conserved aromatic residues are necessary for TspO function: they are thought to be involved in binding porphyrin intermediates . In  the rat mitochondrial peripheral benzodiazepine receptor (MBR) was shown to not only retain its structure within a bacterial outer membrane, but also to be able to functionally substitute for TspO in TspO- mutants, and to act in a similar manner to TspO in its in situ location: the outer mitochondrial membrane. The biological significance of MBR remains unclear, however. It is thought to be involved in a variety of cellular functions, including cholesterol transport in steroidogenic tissues.
Yeliseev AA, Kaplan S; , J Biol Chem 1995;270:21167-21175.: A sensory transducer homologous to the mammalian peripheral-type benzodiazepine receptor regulates photosynthetic membrane complex formation in Rhodobacter sphaeroides 2.4.1. PUBMED:7673149 EPMC:7673149
Yeliseev AA, Kaplan S; , J Biol Chem 2000;275:5657-5667.: TspO of rhodobacter sphaeroides. A structural and functional model for the mammalian peripheral benzodiazepine receptor. PUBMED:10681549 EPMC:10681549
This tab holds annotation information from the InterPro database.
InterPro entry IPR004307
Members of this group are involved in transmembrane signalling. In both prokaryotes and mitochondria they are localized to the outer membrane, and have been shown to bind and transport dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway [ PUBMED:1373486 , PUBMED:7673149 ]. They are associated with the major outer membrane porins (in prokaryotes) and with the voltage-dependent anion channel (in mitochondria) [ PUBMED:8114671 ].
Rhodobacter sphaeroides TspO (previously CrtK) is involved in signal transduction, functioning as a negative regulator of the expression of some photosynthesis genes (PpsR/AppA repressor/antirepressor regulon). This down-regulation is believed to be in response to oxygen levels. TspO works through (or modulates) the PpsR/AppA system and acts upstream of the site of action of these regulatory proteins [ PUBMED:11591680 ]. It has been suggested that the TspO regulatory pathway works by regulating the efflux of certain tetrapyrrole intermediates of the haem/bacteriochlorophyll biosynthetic pathways in response to the availability of molecular oxygen, thereby causing the accumulation of a biosynthetic intermediate that serves as a corepressor for the regulated genes [ PUBMED:10409680 ]. A homologue of the TspO protein in Rhizobium meliloti (Sinorhizobium meliloti) is involved in regulating expression of the ndi locus in response to stress conditions [ PUBMED:11097914 ]. There is evidence that the S. meliloti TspO acts through, or in addition to, the FixL regulatory system.
In animals, translocator protein (TSPO), previously known as peripheral-type benzodiazepine receptor (PBR, MBR) is a mitochondrial protein (located in the outer mitochondrial membrane) where it forms a complex with several proteins of the mitochondrial permeability transition pore (MPTP). TSPO is involved in multiple processes, including regulation of cell death, cholesterol transport and steroid biosynthesis, mitochondrial respiration and oxidation and mitochondrial protein import [ PUBMED:23518318 , PUBMED:22364127 ].
These observations suggest that fundamental aspects of this receptor and the downstream signal transduction pathway are conserved in bacteria and higher eukaryotic mitochondria. The alpha-3 subdivision of the purple bacteria is considered to be a likely source of the endosymbiont that ultimately gave rise to the mitochondrion. Therefore, it is possible that the mammalian PBR remains both evolutionarily and functionally related to the TspO of R. sphaeroides.
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|Cellular component||integral component of membrane (GO:0016021)|
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You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_1882 (release 6.4)|
|Number in seed:||428|
|Number in full:||4730|
|Average length of the domain:||144.30 aa|
|Average identity of full alignment:||27 %|
|Average coverage of the sequence by the domain:||78.77 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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Change the size of the sunburst
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the TspO_MBR domain has been found. There are 21 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
Loading structure mapping...