3VTP

HIV fusion inhibitor MT-C34

Summary for 3VTP

• Entry DOI: 10.2210/pdb3vtp/pdb
• Related: 3VGX 3VIE 3VTQ
• Descriptor: Transmembrane protein gp41 (3 entities in total)
• Functional Keywords: 6-helix-bundle, m-t hook, fusion inhibitor, membrane fusion, viral protein-antiviral protein complex, viral protein/antiviral protein
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Cellular location: Transmembrane protein gp41: Virion membrane; Single-pass type I membrane protein. Surface protein gp120: Virion membrane; Peripheral membrane protein: P03377 P03377
• Total number of polymer chains: 2
• Total formula weight: 9407.60

Authors

Yao, X.,Waltersperger, S.,Wang, M.,Cui, S. (deposition date: 2012-06-02, release date: 2012-08-22, Last modification date: 2024-11-06)

Primary citation

Chong, H.,Yao, X.,Sun, J.,Qiu, Z.,Zhang, M.,Waltersperger, S.,Wang, M.,Cui, S.,He, Y.
The M-T hook structure is critical for design of HIV-1 fusion inhibitors.
J.Biol.Chem., 287:34558-34568, 2012

PubMed 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.

PubMed: 22879603
DOI: 10.1074/jbc.M112.390393

Experimental method

X-RAY DIFFRACTION (1.9 Å)