Gp41

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GP41
SCOP2
2siv / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Gp41 also known as glycoprotein 41 is a subunit of the envelope

HIV vaccines
.

Gene and post-translational modifications

Main article: HIV replication cycle

Gp41 is coded with

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).[1] Once gp160 has been cleaved into its individual subunits, the subunits are then associated non-covalently on the surface of the viral envelope.[citation needed
]

Structure

Gp41 and gp120, when non-covalently bound to each other, are referred to as the envelope spike complex and are formed as a

transmembrane portion of the spike protein complex with a portion of the glycoprotein buried within the viral envelope at all times.[3]

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).[3][4] 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.[3][1] 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.[2]

Function

In a free

metastable and the conformational changes allow gp41 to achieve its more stable active state. Furthermore, these conformational changes are irreversible processes.[8]

HIV-1 fusion process. It involves both subunits of the envelope spike complex. Notably, gp41 is shown in green with its transmembrane region buried in the virion membrane, both segments of heptad repeats (CHR closer to the virus and NHR closer to the host cell) before and after conformational changes, and the N-terminal end of the ectodomain in gray. In the last two panels pointed out by the red arrows, gp41 is observed following penetration of the host cell and following a conformational change resulting in the six-helix bundle which brings the viral and cell membranes into close proximity.

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.[9]

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.[10][11] In developing these drugs, researchers face challenges because the conformation that allows for inhibition occurs very quickly and then rearranges.[12] 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.[3] A variety of naturally occurring molecules have also been shown to bind gp41 and prevent HIV-1 entry.[13]

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).[14] 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.[1] These pockets could potentially serve as targets for small molecule inhibitors.[4] The fusion peptide on the N-terminus of the gp41 is also a potential target because it contains neutralizing antibody epitopes.[15] 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.[12] Small-molecule inhibitors that are able to bind to two hydrophobic pockets at once have also been shown to be 40-60 times more potent and have potential for further developments.[16] Most recently, the gp120-gp41 interface is being considered as a target for bNAbs.[1]

References

  1. ^
    PMID 25760932
    .
  2. ^
    PMID 22864288
    .
  3. ^
    PMID 26957202
    .
  4. ^
    PMID 26324044
    .
  5. S2CID 10544941
    .
  6. S2CID 33914448
    .
  7. PMID 20463810
    .
  8. PMID 25762739
    .
  9. PMID 12637625
    .
  10. PMID 15180542
    .
  11. PMID 26136051
    .
  12. ^
    PMID 26957202
    .
  13. PMID 22264047
    .
  14. PMID 26839147
    .
  15. PMID 27174988
    .
  16. PMID 27908751
    .

External links
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