PDBsum entry 3vtp

Viral protein/antiviral protein

PDB id: 3vtp

Contents

Protein chains

43 a.a.

28 a.a.

Waters ×77

PDB id:

3vtp

Name:

Viral protein/antiviral protein

Title:

HIV fusion inhibitor mt-c34

Structure:

Transmembrane protein gp41. Chain: c. Fragment: n-peptide, unp residues 555-595. Synonym: glycoprotein 41, gp41. Engineered: yes. Transmembrane protein gp41. Chain: d. Fragment: nhr, unp residues 631-666. Synonym: fusion inhibitor mt-c34, glycoprotein 41, gp41.

Source:

Synthetic: yes. Human immunodeficiency virus type 1. HIV-1. Organism_taxid: 11686. Other_details: this sequence occurs naturally in humans.. Other_details: this sequence occurs naturally in humans.

Resolution:

1.90Å R-factor: 0.197 R-free: 0.234

Authors:

X.Yao,S.Waltersperger,M.Wang,S.Cui

Key ref:

H.Chong et al. (2012). The M-T hook structure is critical for design of HIV-1 fusion inhibitors. J Biol Chem, 287, 34558-34568. PubMed id: 22879603

Date:

02-Jun-12 Release date: 22-Aug-12

Protein chain

P03377  (ENV_HV1BR) -  Envelope glycoprotein gp160 from Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI)

Seq: 861 a.a.

Struc: 42 a.a.*

Protein chain

P03377  (ENV_HV1BR) -  Envelope glycoprotein gp160 from Human immunodeficiency virus type 1 group M subtype B (isolate BRU/LAI)

Seq: 861 a.a.

Struc: 27 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

J Biol Chem 287:34558-34568 (2012)

PubMed id: 22879603

The M-T hook structure is critical for design of HIV-1 fusion inhibitors.

H.Chong, X.Yao, J.Sun, Z.Qiu, M.Zhang, S.Waltersperger, M.Wang, S.Cui, Y.He.

ABSTRACT

CP621-652 is a potent HIV-1 fusion inhibitor peptide derived from the C-terminal heptad repeat of gp41. We recently identified that its N-terminal residues Met-626 and Thr-627 adopt a unique hook-like structure (termed M-T hook) thus stabilizing the interaction of the inhibitor with the deep pocket on the N-terminal heptad repeat. In this study, we further demonstrated that the M-T hook structure is a key determinant of CP621-652 in terms of its thermostability and anti-HIV activity. To directly define the structure and function of the M-T hook, we generated the peptide MT-C34 by incorporating Met-626 and Thr-627 into the N terminus of the C-terminal heptad repeat-derived peptide C34. The high resolution crystal structure (1.9 Å) of MT-C34 complexed by an N-terminal heptad repeat-derived peptide reveals that the M-T hook conformation is well preserved at the N-terminal extreme of the inhibitor. Strikingly, addition of two hook residues could dramatically enhance the binding affinity and thermostability of 6-helix bundle core. Compared with C34, MT-C34 exhibited significantly increased activity to inhibit HIV-1 envelope-mediated cell fusion (6.6-fold), virus entry (4.5-fold), and replication (6-fold). Mechanistically, MT-C34 had a 10.5-fold higher increase than C34 in blocking 6-helix bundle formation. We further showed that MT-C34 possessed higher potency against T20 (Enfuvirtide, Fuzeon)-resistant HIV-1 variants. Therefore, this study provides convincing data for our proposed concept that the M-T hook structure is critical for designing HIV-1 fusion inhibitors.