1GZL

Crystal structure of C14linkmid/IQN17: a cross-linked inhibitor of HIV-1 entry bound to the gp41 hydrophobic pocket

Summary for 1GZL

• Entry DOI: 10.2210/pdb1gzl/pdb
• Related: 1DGC 1E7T 1ENV 1FAV 1GCL 1GCM 1GK6 1IHQ 1IJ0 1IJ1 1IJ2 1IJ3 1KQL 1PIQ 1SWI 1TMZ 1YSA 1ZII 1ZIJ 1ZIK 1ZIL 1ZIM 1ZTA 2DGC 2ZTA
• Descriptor: FUSION PROTEIN BETWEEN THE HYDROPHOBIC POCKET OF HIV GP41 AND GENERAL CONTROL PROTEIN GCN4-PIQI, ENVELOPE GLYCOPROTEIN GP41, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: glycoprotein, hiv entry, inhibitor, cross-link, gp41, coiled coil
• Biological source: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST); More
• Total number of polymer chains: 4
• Total formula weight: 14553.81

Authors

Sia, S.K.,Carr, P.A.,Cochran, A.G.,Malashkevich, V.M.,Kim, P.S. (deposition date: 2002-05-23, release date: 2002-10-10, Last modification date: 2024-10-16)

Primary citation

Sia, S.K.,Carr, P.A.,Cochran, A.G.,Malashkevich, V.M.,Kim, P.S.
Short Constrained Peptides that Inhibit HIV-1 Entry
Proc.Natl.Acad.Sci.USA, 99:14664-, 2002

PubMed Abstract: Peptides corresponding to the C-terminal heptad repeat of HIV-1 gp41 (C-peptides) are potent inhibitors of HIV-1 entry into cells. Their mechanism of inhibition involves binding in a helical conformation to the central coiled coil of HIV-1 gp41 in a dominant-negative manner. Short C-peptides, however, have low binding affinity for gp41 and poor inhibitory activity, which creates an obstacle to the development of small drug-like C-peptides. To improve the inhibitory potency of short C-peptides that target the hydrophobic pocket region of gp41, we use two strategies to stabilize the C-peptide helix: chemical crosslinking and substitution with unnatural helix-favoring amino acids. In this study, the short linear peptide shows no significant inhibitory activity, but a constrained peptide (C14linkmid) inhibits cell-cell fusion at micromolar potency. Structural studies confirm that the constrained peptides bind to the gp41 hydrophobic pocket. Calorimetry reveals that, of the peptides analyzed, the most potent are those that best balance the changes in binding enthalpy and entropy, and surprisingly not those with the highest helical propensity as measured by circular dichroism spectroscopy. Our study reveals the thermodynamic basis of inhibition of an HIV C-peptide, demonstrates the utility of constraining methods for a short antiviral peptide inhibitor, and has implications for the future design of constrained peptides.

PubMed: 12417739
DOI: 10.1073/PNAS.232566599

Experimental method

X-RAY DIFFRACTION (1.8 Å)