Summary: Retroviral envelope protein
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Example crystal structures of HIV-1 envelope glycoprotein Gp41
Gp41 also known as glycoprotein 41 is a subunit of the envelope protein complex of retroviruses, including human immunodeficiency virus (HIV). Gp41 is a transmembrane protein that contains several sites within its ectodomain that are required for infection of host cells. As a result of its importance in host cell infection, it has also received much attention as a potential target for HIV vaccines.
Gene and post-translational modifications
Gp41 is coded with gp120 as one gp160 by the env gene of HIV. Gp160 is then extensively glycosylated and proteolytically cleaved by furin, a host cellular protease. The high glycosylation of the env coded glycoproteins allows them to escape the human body's immune system. In contrast to gp120, however, gp41 is less glycosylated and more conserved (less prone to genetic variations). Once gp160 has been cleaved into its individual subunits, the subunits are then associated non-covalently on the surface of the viral envelope.
Gp41 and gp120, when non-covalently bound to each other, are referred to as the envelope spike complex and are formed as a heterotrimer of three gp41 and three gp120. These complexes found on the surface of HIV are responsible for the attachment, fusion, and ultimately the infection of host cells. The structure is cage-like with a hollow center that inhibits antibody access. While gp120 sits on the surface of the viral envelope, gp41 is the transmembrane portion of the spike complex with a portion of the glycoprotein buried within the viral envelope at all times.
Gp41 has three prominent regions within the sequence: the ectodomain, the transmembrane domain, and the cytoplasmic domain. The ectodomain, which comprises residues 511-684, can be further broken down into the fusion peptide region (residues 512-527), the helical N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). In addition to these regions, there is also a loop region that contains disulfide bonds that stabilize the hairpin structure (the folded conformation of gp41) and a region called the membrane proximal external region (MPER) which contains kinks that are antigen target regions. The fusion peptide region is normally buried or hidden by the non-covalent interactions between gp120 and gp41, at a point which looks torus-like. This prevents the fusion peptide from interacting with other regions that are not its intended target region.
In a free virion, the fusion peptides at the amino termini of gp41 are buried within the envelope complex in an inactive non-fusogengic state that is stabilized by a non-covalent bond with gp120. Gp120 binds to a CD4 and a co-receptor (CCR5 or CXCR4), found on susceptible cells such as Helper T cells and macrophages. As a result, a cascade of conformational changes occurs in the gp120 and gp41 proteins. These conformational changes start with gp120 that rearranges to expose the binding sites for the coreceptors mentioned above. The core of gp41 then folds into a six helical bundle (a coiled coil) structure exposing the previously hidden hydrophobic gp41 fusion peptides that are inserted in the host cell membrane allowing fusion to take place. This fusion process is facilitated by the hairpin conformational structure. The inner core of this conformation is 3 NHRs which have hydrophobic pockets that allow it to bind anti-parallel to specific residues on the CHR. The activation process occurs readily, which suggests that the inactive state of gp41 is metastable and the conformational changes allow gp41 to achieve its more stable active state. Furthermore, these conformational changes are irreversible processes.
As a drug target
The interaction of gp41 fusion peptides with the target cell causes a formation of an intermediate, pre-hairpin structure which bridges and fuses the viral and host membranes together. The pre-hairpin structure has a relatively long half-life which makes it a potential target for therapeutic intervention and inhibitory peptides.
Enfuvirtide (also known as T-20) is a 36-residue alpha-peptide fusion inhibitor drug that binds to the pre-hairpin structure and prevents membrane fusion and HIV-1 entry to the cell. The vulnerability of this structure has initiated development towards a whole spectrum of fusion preventing drugs. In developing these drugs, researchers face challenges because the conformation that allows for inhibition occurs very quickly and then rearranges. Enfuviritide specifically has a low oral availability and is quickly processed and expelled by the body. Certain strains of HIV have also developed resistance to T-20. In order to circumvent the difficulties that come with using T-20, researchers have sought out peptide-based inhibitors. A variety of naturally occurring molecules have also been shown to bind gp41 and prevent HIV-1 entry.
The MPER is one region that has been studied as a potential target because of its ability to be recognized by broadly neutralizing antibodies (bNAbs), but it hasn't been a very good target because the immune response it elicits isn't very strong and because it is the portion of gp41 that enters the cell membrane (and it cannot be reached by antibodies then). In addition to antigen binding regions on MPER kinks, there are other targets that could prove to be effective antigen binding regions, including the hydrophobic pockets of the NHR core that is formed following the conformational change in gp41 that creates the six-helix bundle. These pockets could potentially serve as targets for small molecule inhibitors. The fusion peptide on the N-terminus of the gp41 is also a potential target because it contains neutralizing antibody epitopes. N36 and C34, or NHR- and CHR-based peptides (or short sequences of amino acids that mimic portions of gp41) can also act as effective antigens because of their high affinity binding. In addition to having a much higher affinity for binding when compared to its monomer, C34 also inhibits T-20 resistant HIV very well, which makes it a potentially good alternative to treatments involving enfuviritide. Small-molecule inhibitors that are able to bind to two hydrophobic pockets at once have also been show to be 40-60 times more potent and have potential for further developments. Most recently, the gp120-gp41 interface is being considered as a target for bNAbs.
- Wibmer, Constantinos Kurt; Moore, Penny L.; Morris, Lynn. "HIV broadly neutralizing antibody targets". Current Opinion in HIV and AIDS. 10 (3): 135–143. doi:10.1097/coh.0000000000000153. PMC .
- Mao, Youdong; Wang, Liping; Gu, Christopher; Herschhorn, Alon; Xiang, Shi-Hua; Haim, Hillel; Yang, Xinzhen; Sodroski, Joseph. "Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer". Nature Structural & Molecular Biology. 19 (9): 893–899. doi:10.1038/nsmb.2351. PMC . PMID 22864288.
- Yi, Hyun A.; Fochtman, Brian C.; Rizzo, Robert C.; Jacobs, Amy (2016-01-01). "Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41". Current HIV research. 14 (3): 283–294. doi:10.2174/1570162x14999160224103908. ISSN 1873-4251. PMC . PMID 26957202.
- Lu, Lu; Yu, Fei; Cai, Lifeng; Debnath, Asim; Jiang, Shibo. "Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41". Current Topics in Medicinal Chemistry. 16 (10): 1074–1090. doi:10.2174/1568026615666150901114527.
- Chan DC, Kim PS (May 1998). "HIV entry and its inhibition". Cell. 93 (5): 681–4. doi:10.1016/S0092-8674(00)81430-0. PMID 9630213.
- Nomura, Wataru; Mizuguchi, Takaaki; Tamamura, Hirokazu (2016-07-01). "Multimerized HIV-gp41-derived peptides as fusion inhibitors and vaccines". Peptide Science. 106 (4): 622–628. doi:10.1002/bip.22782. ISSN 1097-0282.
- Buzon V, Natrajan G, Schibli D, Campelo F, Kozlov MM, Weissenhorn W (May 2010). "Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions". PLoS Pathogens. 6 (5): e1000880. doi:10.1371/journal.ppat.1000880. PMC . PMID 20463810.
- Munro, James B.; Mothes, Walther (2015-06-01). "Structure and Dynamics of the Native HIV-1 Env Trimer". Journal of Virology. 89 (11): 5752–5755. doi:10.1128/JVI.03187-14. ISSN 0022-538X. PMC . PMID 25762739.
- Lalezari JP, Henry K, O'Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, Cohen C, Kuritzkes DR, Eron JJ, Chung J, DeMasi R, Donatacci L, Drobnes C, Delehanty J, Salgo M (May 2003). "Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America". The New England Journal of Medicine. 348 (22): 2175–85. doi:10.1056/NEJMoa035026. PMID 12637625.
- Root MJ, Steger HK (2004). "HIV-1 gp41 as a target for viral entry inhibition". Current Pharmaceutical Design. 10 (15): 1805–25. doi:10.2174/1381612043384448. PMID 15180542.
- Werner, Halina M; Horne, W Seth (2015-10-01). "Folding and function in α/β-peptides: targets and therapeutic applications". Current Opinion in Chemical Biology. Synthetic biology • Synthetic biomolecules. 28: 75–82. doi:10.1016/j.cbpa.2015.06.013. PMC . PMID 26136051.
- Yi HA, Fochtman BC, Rizzo RC, Jacobs A (2016-01-01). "Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41". Current HIV Research. 14 (3): 283–94. doi:10.2174/1570162x14999160224103908. PMC . PMID 26957202.
- Eade CR, Wood MP, Cole AM (January 2012). "Mechanisms and modifications of naturally occurring host defense peptides for anti-HIV microbicide development". Current HIV Research. 10 (1): 61–72. doi:10.2174/157016212799304580. PMC . PMID 22264047.
- Ghose, Chandrabali; Eugenis, Ioannis; Sun, Xingmin; Edwards, Adrianne N.; McBride, Shonna M.; Pride, David T.; Kelly, Ciarán P.; Ho, David D. (2016-02-03). "Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC". Emerging Microbes & Infections. 5 (2): e8. doi:10.1038/emi.2016.8. PMC . PMID 26839147.
- Kong, Rui; Xu, Kai; Zhou, Tongqing; Acharya, Priyamvada; Lemmin, Thomas; Liu, Kevin; Ozorowski, Gabriel; Soto, Cinque; Taft, Justin D. (2016-05-13). "Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody". Science. 352 (6287): 828–833. doi:10.1126/science.aae0474. ISSN 0036-8075. PMC . PMID 27174988.
- Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A.; Hogan, Priscilla A.; Ptak, Roger G.; Hwang, Peter; Gochin, Miriam (2017-01-01). "Enhanced potency of bivalent small molecule gp41 inhibitors". Bioorganic & Medicinal Chemistry. 25 (1): 408–420. doi:10.1016/j.bmc.2016.11.010. PMC . PMID 27908751.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Retroviral envelope protein Provide feedback
This family includes envelope protein from a variety of retroviruses. It includes the GP41 subunit of the envelope protein complex from human and simian immunodeficiency viruses (HIV and SIV) which mediate membrane fusion during viral entry. The family also includes bovine immunodeficiency virus, feline immunodeficiency virus and Equine infectious anaemia (EIAV). The family also includes the Gp36 protein from mouse mammary tumour virus (MMTV) and human endogenous retroviruses (HERVs).
Malashkevich VN, Chan DC, Chutkowski CT, Kim PS; , Proc Natl Acad Sci USA 1998;95:9134-9139.: Crystal structure of the simian immunodeficiency virus (SIV) gp41 core: conserved helical interactions underlie the broad inhibitory activity of gp41 peptides. PUBMED:9689046 EPMC:9689046
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000328
This entry represents envelope proteins from a variety of retroviruses. It includes the GP41 subunit of the envelope protein complex from Human immunodeficiency virus (HIV) and Simian-Human immunodeficiency virus (SIV), which mediate membrane fusion during viral entry [PUBMED:9689046]. It has a core composed of a six-helix bundle and is folded by its trimeric N- and C-terminal heptad-repeats (NHR and CHR) [PUBMED:18417584]. Derivatives of this protein prevent HIV-1 from entering cell lines and primary human CD4+ cells in vitro [PUBMED:18449216], making it an attractive subject of gene therapy studies against HIV and related retroviruses.
The entry also represents envelope proteins from Bovine immunodeficiency virus, Feline immunodeficiency virus and Equine infectious anemia virus (EIAV) [PUBMED:2841805, PUBMED:10790112], as well as the Gp36 protein from Mouse mammary tumor virus (MMTV) [PUBMED:18625476] and Human endogenous retrovirus (HERV).
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||viral envelope (GO:0019031)|
|Molecular function||structural molecule activity (GO:0005198)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
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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.
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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.
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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_44 (release 1.0)|
|Author:||Finn RD , Bateman A|
|Number in seed:||4|
|Number in full:||84|
|Average length of the domain:||183.60 aa|
|Average identity of full alignment:||27 %|
|Average coverage of the sequence by the domain:||28.66 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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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.
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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.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 GP41 domain has been found. There are 355 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.
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