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Structural and functional characterization of HIV-1 cell fusion inhibitor T20. 2019

Xiujuan Zhang, and Xiaohui Ding, and Yuanmei Zhu, and Huihui Chong, and Sheng Cui, and Jinsheng He, and Xinquan Wang, and Yuxian He
MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology and Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College.

The peptide drug T20 (enfuvirtide), derived from the C-terminal heptad repeat region of HIV-1 gp41, is the only membrane fusion inhibitor available for treatment of viral infection; however, its mechanism of action remains elusive and its structural basis is lacking. We focused on determining the crystal structure of T20 in complex with N39, a target mimic peptide derived from the N-terminal heptad repeat region of gp41. On the basis of the structural information, the mechanisms of action of T20 and its resistance were further characterized. A panel of peptides was synthesized. The T20/N39 complex was assembled for crystallization studies. Circular dichroism spectroscopy, isothermal titration calorimetry (ITC), native polyacrylamide gel electrophoresis (N-PAGE), and mutational analysis were applied to analyze the structural and functional properties. A crystal structure of six-helical bundle (6-HB) structure formed by T20 and N39 was determined with a resolution limit of 2.3 Å, which revealed the critical intrahelical and interhelical interactions underlying the mechanism of action of T20 and its resistance mutations. Although the structural properties in the C-terminal tryptophan-rich motif (TRM) of T20 and the fusion peptide proximal region (FPPR) of N39 could not be finely defined by the structure, the data from biophysical and mutational analyses verified the essential roles of the TRM and FPPR motifs for the binding and inhibitory activities of T20. For the first time, our studies provide a structural basis of T20, which help our understanding on the mechanisms of HIV-1 fusion and its inhibition.

UI MeSH Term Description Entries
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D002151 Calorimetry The measurement of the quantity of heat involved in various processes, such as chemical reactions, changes of state, and formations of solutions, or in the determination of the heat capacities of substances. The fundamental unit of measurement is the joule or the calorie (4.184 joules). (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)
D002942 Circular Dichroism A change from planar to elliptic polarization when an initially plane-polarized light wave traverses an optically active medium. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) Circular Dichroism, Vibrational,Dichroism, Circular,Vibrational Circular Dichroism
D004252 DNA Mutational Analysis Biochemical identification of mutational changes in a nucleotide sequence. Mutational Analysis, DNA,Analysis, DNA Mutational,Analyses, DNA Mutational,DNA Mutational Analyses,Mutational Analyses, DNA
D004591 Electrophoresis, Polyacrylamide Gel Electrophoresis in which a polyacrylamide gel is used as the diffusion medium. Polyacrylamide Gel Electrophoresis,SDS-PAGE,Sodium Dodecyl Sulfate-PAGE,Gel Electrophoresis, Polyacrylamide,SDS PAGE,Sodium Dodecyl Sulfate PAGE,Sodium Dodecyl Sulfate-PAGEs
D000077560 Enfuvirtide A synthetic 36-amino acid peptide that corresponds to the heptad repeat sequence of HIV-1 gp41. It blocks HIV cell fusion and viral entry and is used with other anti-retrovirals for combination therapy of HIV INFECTIONS and AIDS. DP 178,DP-178,DP178,Fuzeon,Pentafuside,Peptide T20,T20 Peptide,T20, Peptide
D053586 Virus Internalization The entering of cells by viruses following VIRUS ATTACHMENT. This is achieved by ENDOCYTOSIS, by translocation of the whole virus across the cell membrane, by direct MEMBRANE FUSION of the viral membrane with the CELL MEMBRANE, or by fusion of the membrane of infected cells with the membrane of non-infected cells causing SYNCYTIA to be formed. Viral Entry,Viral Internalization,Viral Membrane Fusion,Virus Entry,Virus Membrane Fusion,Entry, Viral,Entry, Virus,Fusion, Viral Membrane,Internalization, Viral,Internalization, Virus,Membrane Fusion, Viral
D018360 Crystallography, X-Ray The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) X-Ray Crystallography,Crystallography, X Ray,Crystallography, Xray,X Ray Crystallography,Xray Crystallography,Crystallographies, X Ray,X Ray Crystallographies
D023581 HIV Fusion Inhibitors Inhibitors of the fusion of HIV to host cells, preventing viral entry. This includes compounds that block attachment of HIV ENVELOPE PROTEIN GP120 to CD4 RECEPTORS. Fusion Inhibitors, HIV,HIV Cell Fusion Inhibitor,HIV Entry Inhibitor,HIV Entry Inhibitors,HIV Fusion Inhibitor,HIV Fusion Protein Inhibitor,HIV Cell Fusion Inhibitors,HIV Fusion Protein Inhibitors,Entry Inhibitor, HIV,Entry Inhibitors, HIV,Fusion Inhibitor, HIV,Inhibitor, HIV Entry,Inhibitor, HIV Fusion
D024882 Drug Resistance, Viral The ability of viruses to resist or to become tolerant to chemotherapeutic agents or antiviral agents. This resistance is acquired through gene mutation. Antiviral Drug Resistance,Antiviral Drug Resistances,Drug Resistances, Viral

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