Investigating protein-ligand interactions with a mutant FKBP possessing a designed specificity pocket. Export

@article{citeulike:4087434, abstract = {Using structure-based design and protein mutagenesis we have remodeled the FKBP12 ligand binding site to include a sizable, hydrophobic specificity pocket. This mutant (F36V-FKBP) is capable of binding, with low or subnanomolar affinities, novel synthetic ligands possessing designed substituents that sterically prevent binding to the wild-type protein. Using binding and structural analysis of bumped compounds, we show here that the pocket is highly promiscuous-capable of binding a range of hydrophobic alkyl and aryl moieties with comparable affinity. Ligand affinity therefore appears largely insensitive to the degree of occupancy or quality of packing of the pocket. NMR spectroscopic analysis indicates that similar ligands can adopt radically different binding modes, thus complicating the interpretation of structure-activity relationships.}, author = {Yang, W. and Rozamus, L. W. and Narula, S. and Rollins, C. T. and Yuan, R. and Andrade, L. J. and Ram, M. K. and Phillips, T. B. and van Schravendijk, M. R. and Dalgarno, D. and Clackson, T. and Holt, D. A.}, citeulike-article-id = {4087434}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/10737745}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=10737745}, day = {23}, issn = {0022-2623}, journal = {Journal of medicinal chemistry}, keywords = {fkbp, h, ifgfr}, month = {March}, number = {6}, pages = {1135--1142}, posted-at = {2009-03-03 22:24:41}, priority = {2}, title = {Investigating protein-ligand interactions with a mutant FKBP possessing a designed specificity pocket.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/10737745}, volume = {43}, year = {2000} }

TY - JOUR ID - citeulike:4087434 L3 - citeulike-article-id:4087434 N2 - Using structure-based design and protein mutagenesis we have remodeled the FKBP12 ligand binding site to include a sizable, hydrophobic specificity pocket. This mutant (F36V-FKBP) is capable of binding, with low or subnanomolar affinities, novel synthetic ligands possessing designed substituents that sterically prevent binding to the wild-type protein. Using binding and structural analysis of bumped compounds, we show here that the pocket is highly promiscuous-capable of binding a range of hydrophobic alkyl and aryl moieties with comparable affinity. Ligand affinity therefore appears largely insensitive to the degree of occupancy or quality of packing of the pocket. NMR spectroscopic analysis indicates that similar ligands can adopt radically different binding modes, thus complicating the interpretation of structure-activity relationships. IS - 6 JF - Journal of medicinal chemistry SN - 0022-2623 EP - 1142 TI - Investigating protein-ligand interactions with a mutant FKBP possessing a designed specificity pocket. VL - 43 SP - 1135 KW - fkbp KW - h KW - ifgfr AU - Yang, W AU - Rozamus, LW AU - Narula, S AU - Rollins, CT AU - Yuan, R AU - Andrade, LJ AU - Ram, MK AU - Phillips, TB AU - van Schravendijk, MR AU - Dalgarno, D AU - Clackson, T AU - Holt, DA PY - 2000/03/23/ UR - http://view.ncbi.nlm.nih.gov/pubmed/10737745 ER -