PDBsum entry 1qr9

Viral protein

PDB id

1qr9

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Contents

			Protein chain

					68 a.a. *

			Waters ×49

* Residue conservation analysis

PDB id:

1qr9

Links

Name:

Viral protein

Title:

Inhibition of HIV-1 infectivity by the gp41 core: role of a conserved hydrophobic cavity in membrane fusion

Structure:

Gp41 envelope protein. Chain: a. Fragment: subdomain n34(l6)c28. Mutation: yes

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676

Biol. unit:

Trimer (from PDB file)

Resolution:

1.60Å

R-factor:

0.202

R-free:

0.261

Authors:

H.Ji,W.Shu,F.T.Burling,S.B.Jiang,M.Lu

Key ref:

H.Ji et al. (1999). Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core: role of a conserved hydrophobic cavity in membrane fusion. J Virol, 73, 8578-8586. PubMed id: 10482611

Date:

18-Jun-99

Release date:

26-Nov-99

PROCHECK

	Headers

	References

Protein chain

Q76270 (Q76270_HV1) - Env polyprotein (Fragment) from Human immunodeficiency virus type 1

Seq: Struc:					124 a.a. 68 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 35 residue positions (black crosses)

	J Virol 73:8578-8586 (1999)
PubMed id: 10482611

Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core: role of a conserved hydrophobic cavity in membrane fusion.
H.Ji, W.Shu, F.T.Burling, S.Jiang, M.Lu.

ABSTRACT

The gp41 envelope protein of human immunodeficiency virus type 1 (HIV-1) contains an alpha-helical core structure responsible for mediating membrane fusion during viral entry. Recent studies suggest that a conserved hydrophobic cavity in the coiled coil of this core plays a distinctive structural role in maintaining the fusogenic conformation of the gp41 molecule. Here we investigated the importance of this cavity in determining the structure and biological activity of the gp41 core by using the N34(L6)C28 model. The high-resolution crystal structures of N34(L6)C28 of two HIV-1 gp41 fusion-defective mutants reveal that each mutant sequence is accommodated in the six-helix bundle structure by forming the cavity with different sets of atoms. Remarkably, the mutant N34(L6)C28 cores are highly effective inhibitors of HIV-1 infection, with 5- to 16-fold greater activity than the wild-type molecule. The enhanced inhibitory activity by fusion-defective mutations correlates with local structural perturbations close to the cavity that destabilize the six-helix bundle. Taken together, these results indicate that the conserved hydrophobic coiled-coil cavity in the gp41 core is critical for HIV-1 entry and its inhibition and provides a potential antiviral drug target.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21258789

A.Ashkenazi, and Y.Shai (2011).
Insights into the mechanism of HIV-1 envelope induced membrane fusion as revealed by its inhibitory peptides.

Eur Biophys J, 40, 349-357.

19827030

M.I.Qadir, and S.A.Malik (2010).
HIV fusion inhibitors.

Rev Med Virol, 20, 23-33.

19254359

M.P.Chien, C.H.Lin, and D.K.Chang (2009).
Recruitment of HIV-1 envelope occurs subsequent to lipid mixing: a fluorescence microscopic evidence.

Retrovirology, 6, 20.

19114674

T.Naito, K.Izumi, E.Kodama, Y.Sakagami, K.Kajiwara, H.Nishikawa, K.Watanabe, S.G.Sarafianos, S.Oishi, N.Fujii, and M.Matsuoka (2009).
SC29EK, a peptide fusion inhibitor with enhanced alpha-helicity, inhibits replication of human immunodeficiency virus type 1 mutants resistant to enfuvirtide.

Antimicrob Agents Chemother, 53, 1013-1018.

18768964

Y.He, S.Liu, J.Li, H.Lu, Z.Qi, Z.Liu, A.K.Debnath, and S.Jiang (2008).
Conserved salt bridge between the N- and C-terminal heptad repeat regions of the human immunodeficiency virus type 1 gp41 core structure is critical for virus entry and inhibition.

J Virol, 82, 11129-11139.

18662985

Z.Qi, W.Shi, N.Xue, C.Pan, W.Jing, K.Liu, and S.Jiang (2008).
Rationally designed anti-HIV peptides containing multifunctional domains as molecule probes for studying the mechanisms of action of the first and second generation HIV fusion inhibitors.

J Biol Chem, 283, 30376-30384.

17335007

B.Strockbine, and R.C.Rizzo (2007).
Binding of antifusion peptides with HIVgp41 from molecular dynamics simulations: quantitative correlation with experiment.

Proteins, 67, 630-642.

17251293

L.E.Luque, and C.J.Russell (2007).
Spring-loaded heptad repeat residues regulate the expression and activation of paramyxovirus fusion protein.

J Virol, 81, 3130-3141.

17428857

R.Chinnadurai, D.Rajan, J.Münch, and F.Kirchhoff (2007).
Human immunodeficiency virus type 1 variants resistant to first- and second-version fusion inhibitors and cytopathic in ex vivo human lymphoid tissue.

J Virol, 81, 6563-6572.

16515685

D.Delcroix-Genête, P.L.Quan, M.G.Roger, U.Hazan, S.Nisole, and C.Rousseau (2006).
Antiviral properties of two trimeric recombinant gp41 proteins.

Retrovirology, 3, 16.

16492145

W.M.Kazmierski, T.P.Kenakin, and K.S.Gudmundsson (2006).
Peptide, peptidomimetic and small-molecule drug discovery targeting HIV-1 host-cell attachment and entry through gp120, gp41, CCR5 and CXCR4.

Chem Biol Drug Des, 67, 13-26.

16827565

Y.Xu, H.Lu, J.P.Kennedy, X.Yan, L.A.McAllister, N.Yamamoto, J.A.Moss, G.E.Boldt, S.Jiang, and K.D.Janda (2006).
Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation.

J Comb Chem, 8, 531-539.

16092970

W.Ou, and J.Silver (2005).
Efficient trapping of HIV-1 envelope protein by hetero-oligomerization with an N-helix chimera.

Retrovirology, 2, 51.

15066182

T.Krell, F.Greco, O.Engel, J.Dubayle, J.Dubayle, A.Kennel, B.Charloteaux, R.Brasseur, M.Chevalier, R.Sodoyer, and R.El Habib (2004).
HIV-1 gp41 and gp160 are hyperthermostable proteins in a mesophilic environment. Characterization of gp41 mutants.

Eur J Biochem, 271, 1566-1579.

14694135

T.Murakami, S.Ablan, E.O.Freed, and Y.Tanaka (2004).
Regulation of human immunodeficiency virus type 1 Env-mediated membrane fusion by viral protease activity.

J Virol, 78, 1026-1031.

12631714

R.M.Markosyan, F.S.Cohen, and G.B.Melikyan (2003).
HIV-1 envelope proteins complete their folding into six-helix bundles immediately after fusion pore formation.

Mol Biol Cell, 14, 926-938.

12610147

S.Giannecchini, A.Di Fenza, A.M.D'Ursi, D.Matteucci, P.Rovero, and M.Bendinelli (2003).
Antiviral activity and conformational features of an octapeptide derived from the membrane-proximal ectodomain of the feline immunodeficiency virus transmembrane glycoprotein.

J Virol, 77, 3724-3733.

12072535

K.E.Follis, S.J.Larson, M.Lu, and J.H.Nunberg (2002).
Genetic evidence that interhelical packing interactions in the gp41 core are critical for transition of the human immunodeficiency virus type 1 envelope glycoprotein to the fusion-active state.

J Virol, 76, 7356-7362.

12097573

N.Boutonnet, W.Janssens, C.Boutton, J.L.Verschelde, L.Heyndrickx, E.Beirnaert, G.van der Groen, and I.Lasters (2002).
Comparison of predicted scaffold-compatible sequence variation in the triple-hairpin structure of human imunodeficiency virus type 1 gp41 with patient data.

J Virol, 76, 7595-7606.

11863433

X.Siebert, and G.Hummer (2002).
Hydrophobicity maps of the N-peptide coiled coil of HIV-1 gp41.

Biochemistry, 41, 2956-2961.

11258890

J.Liu, W.Shu, M.B.Fagan, J.H.Nunberg, and M.Lu (2001).
Structural and functional analysis of the HIV gp41 core containing an Ile573 to Thr substitution: implications for membrane fusion.

Biochemistry, 40, 2797-2807.

PDB code:

1f23

11602754

M.Lu, M.O.Stoller, S.Wang, J.Liu, M.B.Fagan, and J.H.Nunberg (2001).
Structural and functional analysis of interhelical interactions in the human immunodeficiency virus type 1 gp41 envelope glycoprotein by alanine-scanning mutagenesis.

J Virol, 75, 11146-11156.

PDB codes:

1i5x 1i5y

11260595

M.Triantafilou, K.M.Wilson, and K.Triantafilou (2001).
Identification of Echovirus 1 and coxsackievirus A9 receptor molecules via a novel flow cytometric quantification method.

Cytometry, 43, 279-289.

11242518

P.W.Mobley, R.Pilpa, C.Brown, A.J.Waring, and L.M.Gordon (2001).
Membrane-perturbing domains of HIV type 1 glycoprotein 41.

AIDS Res Hum Retroviruses, 17, 311-327.

10651632

H.Ji, C.Bracken, and M.Lu (2000).
Buried polar interactions and conformational stability in the simian immunodeficiency virus (SIV) gp41 core.

Biochemistry, 39, 676-685.

10677212

W.Shu, J.Liu, H.Ji, L.Radigen, S.Jiang, and M.Lu (2000).
Helical interactions in the HIV-1 gp41 core reveal structural basis for the inhibitory activity of gp41 peptides.

Biochemistry, 39, 1634-1642.

PDB code:

1dlb

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.