5H0N
Crystal structure of HIV-1 fusion inhibitor MT-WQ-IDL bound to gp41 NHR
Summary for 5H0N
| Entry DOI | 10.2210/pdb5h0n/pdb |
| Descriptor | HIV-1 gp41 NHR, HIV-1 fusion inhibitor MT-WQ-IDL (3 entities in total) |
| Functional Keywords | mt-wq-idl, hiv-1, fusion inhibitor, viral protein-viral protein inhibitor complex, viral protein/viral protein inhibitor |
| Biological source | Human immunodeficiency virus 1 More |
| Total number of polymer chains | 12 |
| Total formula weight | 55101.65 |
| Authors | |
| Primary citation | Su, S.,Zhu, Y.,Ye, S.,Qi, Q.,Xia, S.,Ma, Z.,Yu, F.,Wang, Q.,Zhang, R.,Jiang, S.,Lu, L. Creating an Artificial Tail Anchor as a Novel Strategy To Enhance the Potency of Peptide-Based HIV Fusion Inhibitors J. Virol., 91:-, 2017 Cited by PubMed Abstract: 20 (enfuvirtide) and other peptides derived from the human immunodeficiency virus type 1 (HIV-1) gp41 C-terminal heptad repeat (CHR) region inhibit HIV fusion by binding to the hydrophobic grooves on the N-terminal heptad repeat (NHR) trimer and blocking six-helix-bundle (6-HB) formation. Several strategies focusing on the binding grooves of the NHR trimer have been adopted to increase the antiviral activity of the CHR peptides. Here, we developed a novel and simple strategy to greatly enhance the potency of the existing peptide-based HIV fusion inhibitors. First, we identified a shallow pocket adjacent to the groove in the N-terminal region of NHR trimer as a new drug target, and then we designed several short artificial peptides to fit this target. After the addition of IDL (Ile-Asp-Leu) to the C terminus of CHR peptide WQ or MT-WQ, the conjugated peptides, WQ-IDL and MT-WQ-IDL, showed much more potent activities than WQ and T20, respectively, in inhibiting HIV-1 IIIB infection. WQ-IDL and MT-WQ-IDL were also more effective than WQ in blocking HIV-1 Env-mediated membrane fusion and had higher levels of binding affinity with NHR peptide N46. We solved the crystal structure of the 6-HB formed by MT-WQ-IDL and N46 and found that, besides the N-terminal MT hook tail, the IDL tail anchor of MT-WQ-IDL also binds with the shallow hydrophobic pocket outside the groove of the NHR trimer, resulting in enhanced inhibition of HIV-1 fusion with the target cell. It is expected that this novel approach can be widely used to improve the potency of peptidic fusion inhibitors against other enveloped viruses with class I fusion proteins. PubMed: 27795416DOI: 10.1128/JVI.01445-16 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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