5YC0
Crystal structure of LP-46/N44
Summary for 5YC0
| Entry DOI | 10.2210/pdb5yc0/pdb |
| Descriptor | Envelope glycoprotein, LP-46 (3 entities in total) |
| Functional Keywords | 6-hb, hiv-1, viral protein-inhibitor complex, viral protein/inhibitor |
| Biological source | Human immunodeficiency virus 1 More |
| Total number of polymer chains | 12 |
| Total formula weight | 53587.16 |
| Authors | |
| Primary citation | Zhu, Y.,Zhang, X.,Ding, X.,Chong, H.,Cui, S.,He, J.,Wang, X.,He, Y. Exceptional potency and structural basis of a T1249-derived lipopeptide fusion inhibitor against HIV-1, HIV-2, and simian immunodeficiency virus J. Biol. Chem., 293:5323-5334, 2018 Cited by PubMed Abstract: Enfuvirtide (T20) is the only viral fusion inhibitor approved for clinical use, but it has relatively weak anti-HIV activity and easily induces drug resistance. In succession to T20, T1249 has been designed as a 39-mer peptide composed of amino acid sequences derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV); however, its development has been suspended due to formulation difficulties. We recently developed a T20-based lipopeptide (LP-40) showing greatly improved pharmaceutical properties. Here, we generated a T1249-based lipopeptide, termed LP-46, by replacing its C-terminal tryptophan-rich sequence with fatty acid. As compared with T20, T1249, and LP-40, the truncated LP-46 (31-mer) had dramatically increased activities in inhibiting a large panel of HIV-1 subtypes, with IC values approaching low picomolar concentrations. Also, LP-46 was an exceptionally potent inhibitor against HIV-2, SIV, and T20-resistant variants, and it displayed obvious synergistic effects with LP-40. Furthermore, we showed that LP-46 had increased helical stability and binding affinity with the target site. The crystal structure of LP-46 in complex with a target surrogate revealed its critical binding motifs underlying the mechanism of action. Interestingly, it was found that the introduced pocket-binding domain in LP-46 did not interact with the gp41 pocket as expected; instead, it adopted a mode similar to that of LP-40. Therefore, our studies have provided an exceptionally potent and broad fusion inhibitor for developing new anti-HIV drugs, which can also serve as a tool to exploit the mechanisms of viral fusion and inhibition. PubMed: 29425101DOI: 10.1074/jbc.RA118.001729 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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