Limits...
High-resolution structure of a retroviral protease folded as a monomer.

Gilski M, Kazmierczyk M, Krzywda S, Zábranská H, Cooper S, Popović Z, Khatib F, DiMaio F, Thompson J, Baker D, Pichová I, Jaskolski M - Acta Crystallogr. D Biol. Crystallogr. (2011)

Bottom Line: The flap has an unusual curled shape and a different orientation from both the open and closed states known from dimeric retropepsins.The overall fold of the protein follows the retropepsin canon, but the C(α) deviations are large and the active-site 'DTG' loop (here NTG) deviates up to 2.7 Å from the standard conformation.This structure of a monomeric retropepsin determined at high resolution (1.6 Å) provides important extra information for the design of dimerization inhibitors that might be developed as drugs for the treatment of retroviral infections, including AIDS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.

Show MeSH

Related in: MedlinePlus

Alignment of retroviral proteases. (a) Stereoview of the superposition of the Cα traces of protomers of retroviral proteases: green and blue, M-PMV (A and B); red, HIV-1, apo form (PDB entry 3hvp); orange, HIV-1, inhibitor complex (PDB entry 4hvp); lime, EIAV (PDB entry 2fmb); grey, M-PMV, NMR model (PDB entry 1nso), energy-minimized (in water). (b) Structure-based sequence alignment of the M-PMV, EIAV (PDB entry 2fmb; lowest core Cα r.m.s.d.; Table 2 ▶), FIV (PDB entry 4fiv; highest level of sequence identity – 26.6%) and HIV-1 (PDB entry 3hvp) proteases. Residue numbers and secondary-structure elements (arrows, β-strands; blue, α-helices; green, 310-helices; yellow, flap loops) are marked for the M-­PMV and HIV-1 proteases. Residues that are identical in all four sequences are shown on a red background. Disordered residues missing from the M-PMV PR structure are shown in grey.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3211970&req=5

fig2: Alignment of retroviral proteases. (a) Stereoview of the superposition of the Cα traces of protomers of retroviral proteases: green and blue, M-PMV (A and B); red, HIV-1, apo form (PDB entry 3hvp); orange, HIV-1, inhibitor complex (PDB entry 4hvp); lime, EIAV (PDB entry 2fmb); grey, M-PMV, NMR model (PDB entry 1nso), energy-minimized (in water). (b) Structure-based sequence alignment of the M-PMV, EIAV (PDB entry 2fmb; lowest core Cα r.m.s.d.; Table 2 ▶), FIV (PDB entry 4fiv; highest level of sequence identity – 26.6%) and HIV-1 (PDB entry 3hvp) proteases. Residue numbers and secondary-structure elements (arrows, β-strands; blue, α-helices; green, 310-helices; yellow, flap loops) are marked for the M-­PMV and HIV-1 proteases. Residues that are identical in all four sequences are shown on a red background. Disordered residues missing from the M-PMV PR structure are shown in grey.

Mentions: The flap of M-PMV PR (residues Ile45–Ser64; Fig. 2 ▶ b) has a peculiar shape. It is not a smooth hairpin with β-type interactions as in other retropepsins, but has a wide conformation with a 310-helical segment (Gln57–Asn59) present in its C-­terminal part. The flap folds upon the body of the protein but in a way that is different from the ‘lowered’ flap position over the active site of retropepsin dimers in complex with inhibitors (Fig. 2 ▶ a). The flap arm appears to be much shorter because of the helical insertion and its blunt end. The leading/trailing strands follow the ‘lowered’/‘open’ flap traces of HIV-1 PR. The 310-helix in the trailing strand resembles a helical insertion in the flap of HTLV-1 (human T-cell leukaemia virus type-1) PR (Li et al., 2005 ▶).


High-resolution structure of a retroviral protease folded as a monomer.

Gilski M, Kazmierczyk M, Krzywda S, Zábranská H, Cooper S, Popović Z, Khatib F, DiMaio F, Thompson J, Baker D, Pichová I, Jaskolski M - Acta Crystallogr. D Biol. Crystallogr. (2011)

Alignment of retroviral proteases. (a) Stereoview of the superposition of the Cα traces of protomers of retroviral proteases: green and blue, M-PMV (A and B); red, HIV-1, apo form (PDB entry 3hvp); orange, HIV-1, inhibitor complex (PDB entry 4hvp); lime, EIAV (PDB entry 2fmb); grey, M-PMV, NMR model (PDB entry 1nso), energy-minimized (in water). (b) Structure-based sequence alignment of the M-PMV, EIAV (PDB entry 2fmb; lowest core Cα r.m.s.d.; Table 2 ▶), FIV (PDB entry 4fiv; highest level of sequence identity – 26.6%) and HIV-1 (PDB entry 3hvp) proteases. Residue numbers and secondary-structure elements (arrows, β-strands; blue, α-helices; green, 310-helices; yellow, flap loops) are marked for the M-­PMV and HIV-1 proteases. Residues that are identical in all four sequences are shown on a red background. Disordered residues missing from the M-PMV PR structure are shown in grey.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3211970&req=5

fig2: Alignment of retroviral proteases. (a) Stereoview of the superposition of the Cα traces of protomers of retroviral proteases: green and blue, M-PMV (A and B); red, HIV-1, apo form (PDB entry 3hvp); orange, HIV-1, inhibitor complex (PDB entry 4hvp); lime, EIAV (PDB entry 2fmb); grey, M-PMV, NMR model (PDB entry 1nso), energy-minimized (in water). (b) Structure-based sequence alignment of the M-PMV, EIAV (PDB entry 2fmb; lowest core Cα r.m.s.d.; Table 2 ▶), FIV (PDB entry 4fiv; highest level of sequence identity – 26.6%) and HIV-1 (PDB entry 3hvp) proteases. Residue numbers and secondary-structure elements (arrows, β-strands; blue, α-helices; green, 310-helices; yellow, flap loops) are marked for the M-­PMV and HIV-1 proteases. Residues that are identical in all four sequences are shown on a red background. Disordered residues missing from the M-PMV PR structure are shown in grey.
Mentions: The flap of M-PMV PR (residues Ile45–Ser64; Fig. 2 ▶ b) has a peculiar shape. It is not a smooth hairpin with β-type interactions as in other retropepsins, but has a wide conformation with a 310-helical segment (Gln57–Asn59) present in its C-­terminal part. The flap folds upon the body of the protein but in a way that is different from the ‘lowered’ flap position over the active site of retropepsin dimers in complex with inhibitors (Fig. 2 ▶ a). The flap arm appears to be much shorter because of the helical insertion and its blunt end. The leading/trailing strands follow the ‘lowered’/‘open’ flap traces of HIV-1 PR. The 310-helix in the trailing strand resembles a helical insertion in the flap of HTLV-1 (human T-cell leukaemia virus type-1) PR (Li et al., 2005 ▶).

Bottom Line: The flap has an unusual curled shape and a different orientation from both the open and closed states known from dimeric retropepsins.The overall fold of the protein follows the retropepsin canon, but the C(α) deviations are large and the active-site 'DTG' loop (here NTG) deviates up to 2.7 Å from the standard conformation.This structure of a monomeric retropepsin determined at high resolution (1.6 Å) provides important extra information for the design of dimerization inhibitors that might be developed as drugs for the treatment of retroviral infections, including AIDS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Crystallography, Faculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland.

Show MeSH
Related in: MedlinePlus