3VH7

Structure of HIV-1 gp41 NHR/fusion inhibitor complex P21

Summary for 3VH7

• Entry DOI: 10.2210/pdb3vh7/pdb
• Related: 3VGX 3VGY
• Descriptor: Envelope glycoprotein gp160, CP32M, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: 6-helix bundle, membrane fusion inhibition, membrane protein-inhibitor complex, membrane protein/inhibitor
• 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: P03375
• Total number of polymer chains: 6
• Total formula weight: 32151.55

Authors

Yao, X.,Waltersperger, S.,Wang, M.T.,Cui, S. (deposition date: 2011-08-23, release date: 2012-06-13, Last modification date: 2023-11-08)

Primary citation

Yao, X.,Chong, H.,Zhang, C.,Qiu, Z.,Qin, B.,Han, R.,Waltersperger, S.,Wang, M.T.,He, Y.,Cui, S.
Structural basis of potent and broad HIV-1 fusion inhibitor CP32M
J.Biol.Chem., 287:26618-26629, 2012

PubMed Abstract: CP32M is a newly designed peptide fusion inhibitor possessing potent anti-HIV activity, especially against T20-resistant HIV-1 strains. In this study, we show that CP32M can efficiently inhibit a large panel of diverse HIV-1 variants, including subtype B', CRF07_BC, and CRF01_AE recombinants and naturally occurring or induced T20-resistant viruses. To elucidate its mechanism of action, we determined the crystal structure of CP32M complexed with its target sequence. Differing from its parental peptide, CP621-652, the (621)VEWNEMT(627) motif of CP32M folds into two α-helix turns at the N terminus of the pocket-binding domain, forming a novel layer in the six-helix bundle structure. Prominently, the residue Asn-624 of the (621)VEWNEMT(627) motif is engaged in the polar interaction with a hydrophilic ridge that borders the hydrophobic pocket on the N-terminal coiled coil. The original inhibitor design of CP32M provides several intra- and salt bridge/hydrogen bond interactions favoring the stability of the helical conformation of CP32M and its interactions with N-terminal heptad repeat (NHR) targets. We identified a novel salt bridge between Arg-557 on the NHR and Glu-648 of CP32M that is critical for the binding of CP32M and resistance against the inhibitor. Therefore, our data present important information for developing novel HIV-1 fusion inhibitors for clinical use.

PubMed: 22679024
DOI: 10.1074/jbc.M112.381079

Experimental method

X-RAY DIFFRACTION (2.019 Å)