Design and characterization of swapped-domain constructs of HIV-1 glycoprotein-41 as receptors for drug discovery

Protein Engineering, Design & Selection : PEDS
Joseph D WalshMiriam Gochin

Abstract

Four new swapped-domain constructs of the ectodomain of human immunodeficiency virus type 1 glycoprotein-41 (gp41) were prepared. The gp41 ectodomain consists of 50-residue N-heptad repeat (NHR), 36-residue disulfide-bonded loop and 39-residue C-heptad repeat (CHR). It folds into a hairpin structure that forms a trimer along the NHR axis. The swapped-domain proteins feature CHR domains of length 39, 28 or 21 residues preceding a 4-residue loop and a 49- or 50-residue NHR domain. The effect of CHR truncation was to expose increasing lengths of the NHR groove, including the conserved hydrophobic pocket, an important drug target. A novel method for preparing proteins with extended exposed hydrophobic surfaces was demonstrated. Biophysical measurements, including analytical ultracentrifugation and ligand-detected Water-Ligand Observed via Gradient Spectroscopy and (1)H-(15)N-HSQC NMR experiments, were used to confirm that the proteins formed stable trimers in solution with exposed binding surfaces. These proteins could play an important role as receptors in structure-based drug discovery.

References

Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
May 22, 1997·Nature·W WeissenhornD C Wiley
Aug 1, 1997·Protein Science : a Publication of the Protein Society·P T WingfieldG M Clore
Jan 24, 1998·Journal of Biomolecular Structure & Dynamics·M Lu, P S Kim
Aug 26, 1998·The EMBO Journal·M CaffreyG M Clore
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·D C ChanP S Kim
Apr 14, 1999·Nature Structural Biology·M PellecchiaR Glockshuber
Sep 24, 1999·Protein Science : a Publication of the Protein Society·M CaffreyG M Clore
Jun 30, 2000·Protein Expression and Purification·R B Kapust, D S Waugh
May 9, 2001·Biochemistry·J L Cole, V M Garsky
Oct 6, 2005·Proceedings of the National Academy of Sciences of the United States of America·Michael D MillerAntonello Pessi
Jul 25, 2006·Nature Structural & Molecular Biology·Micah A LuftigAndrea Carfí
Feb 13, 2007·Journal of Computer-aided Molecular Design·Kent D StewartAkhter Molla
Jul 21, 2007·Proceedings of the National Academy of Sciences of the United States of America·John J DwyerMary K Delmedico
Jan 17, 2008·Journal of Medicinal Chemistry·Shinya OishiNobutaka Fujii
Jun 19, 2009·Journal of Medicinal Chemistry·Miriam Gochin, Lifeng Cai
Dec 17, 2009·Bioorganic & Medicinal Chemistry Letters·Kent D StewartEdward T Olejniczak
Aug 20, 2010·Journal of Virology·Brett D WelchMichael S Kay
Sep 21, 2011·Journal of Medicinal Chemistry·Guangyan ZhouMiriam Gochin
Mar 20, 2012·Bioorganic & Medicinal Chemistry Letters·Landon R WhitbyDale L Boger
Aug 13, 2013·Bioorganic & Medicinal Chemistry Letters·Shidong Chu, Miriam Gochin
Nov 2, 2013·Science·Jean-Philippe JulienIan A Wilson

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Citations

Sep 6, 2020·Biochimica Et Biophysica Acta. General Subjects·Guangyan ZhouMiriam Gochin
May 7, 2021·Chemical Communications : Chem Comm·Guangyan ZhouMiriam Gochin

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