tailieunhanh - Báo cáo khoa học: Retrocyclin RC-101 overcomes cationic mutations on the heptad repeat 2 region of HIV-1 gp41

Retrocyclin RC-101, ah-defensin with lectin-like properties, potently inhib-its infection by many HIV-1 subtypes by binding to the heptad repeat 2 (HR2) region of glycoprotein 41 (gp41) and preventing six-helix bundle for-mation. | ỊFEBS Journal Retrocyclin RC-101 overcomes cationic mutations on the heptad repeat 2 region of HIV-1 gp41 Christopher A. Fuhrman1 Andrew D. Warren1 Alan J. Waring2 Stephen M. Dutz3 Shantanu Sharma3 Robert I. Lehrer2 Amy L. Cole1 and Alexander M. Cole1 1 Molecular Biology Microbiology Biomolecular Science Center Burnett College of BiomedicalSciences at University of CentralFlorida Orlando FL USA 2 Department of Medicine David Geffen Schoolof Medicine University of California Los Angeles CA USA 3 Department of Chemistry and Center for Macromolecular Modeling Materials Design California State Polytechnic University Pomona CA USA Keywords autodock defensin HIV-1 innate immunity retrocyclin Correspondence A. M. Cole Department. of Molecular Biology Microbiology Burnett School of BiomedicalSciences University of Central Florida 4000 CentralFlorida Boulevard Building 20 Room 236 Orlando FL 32816 USA Fax 1 407 823 3635 Tel 1 407 823 3633 E-mail acole@ Received 8 August 2007 revised 24 October 2007 accepted 25 October 2007 doi Retrocyclin RC-101 a 0-defensin with lectin-like properties potently inhibits infection by many HIV-1 subtypes by binding to the heptad repeat 2 HR2 region of glycoprotein 41 gp41 and preventing six-helix bundle formation. In the present study we used in silico computational exploration to identify residues of HR2 that interacted with RC-101 and then analyzed the HIV-1 sequence database at Los Alamos National Laboratory New Mexico USA for residue variations in the heptad repeat 1 HR1 and HR2 segments that could plausibly impart in vivo resistance. Docking RC-101 to gp41 peptides in silico confirmed its strong preference for HR2 over HR1 and implicated residues crucial for its ability to bind HR2. We mutagenized these residues in pseudotyped HIV-1 reporter viruses and subjected them to single-round replication assays in the presence of Ltg-mL 1 RC-101. Apart from one mutant that was partially .

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