Exploring the Binding Site Structure of the PPARγ Ligand-Binding Domain by
Computational Solvent Mapping<sup>†</sup>
Shu-Hsien Sheu
Taner Kaya
David J. Waxman
Sandor Vajda
10.1021/bi048032c.s005
https://acs.figshare.com/articles/dataset/Exploring_the_Binding_Site_Structure_of_the_PPAR_Ligand_Binding_Domain_by_Computational_Solvent_Mapping_sup_sup_/3302878
Solvent mapping moves molecular probes, small organic molecules containing various functional
groups, around the protein surface, finds favorable positions, clusters the conformations, and ranks the
clusters based on the average free energy. Using at least six different solvents as probes, the probes
cluster in major pockets of the functional site, providing detailed and reliable information on the amino
acid residues that are important for ligand binding. Solvent mapping was applied to 12 structures of the
peroxisome proliferator activated receptor γ (PPARγ) ligand-binding domain (LBD), including 2 structures
without a ligand, 2 structures with a partial agonist, and 8 structures with a PPAR agonist bound. The
analysis revealed 10 binding “hot spots”, 4 in the ligand-binding pocket, 2 in the coactivator-binding
region, 1 in the dimerization domain, 2 around the ligand entrance site, and 1 minor site without a known
function. Mapping is a major source of information on the role and cooperativity of these sites. It shows
that large portions of the ligand-binding site are already formed in the PPARγ apostructure, but an important
pocket near the AF-2 transactivation domain becomes accessible only in structures that are cocrystallized
with strong agonists. Conformational changes were seen in several other sites, including one involved in
the stabilization of the LBD and two others at the region of the coactivator binding. The number of probe
clusters retained by these sites depends on the properties of the bound agonist, providing information on
the origin of correlations between ligand and coactivator binding.
2005-02-01 00:00:00
PPAR γ apostructure
LBD
probe
AF
ligand entrance site
agonist
coactivator binding
Binding Site Structure
cluster
Solvent
information
2 structures