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Shape‐shifting proteins with a potential link to drug side effects
Author(s) -
Lawrence Sarah H,
Selwood Trevor,
Ramirez Ursula D.,
Stith Linda,
Jaffe Eileen K
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.907.5
Subject(s) - random hexamer , chemistry , in silico , in vitro , dimer , stereochemistry , in vivo , drug discovery , drug , biochemistry , biophysics , pharmacology , biology , genetics , gene , organic chemistry
Human porphobilinogen synthase (huPBGS, EC 4.2.1.24) exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. Reduced huPBGS activity factors in the disease states lead poisoning and ALAD porphyria, the latter of which involves hexamer‐favoring huPBGS variants. The Jaffe lab has established that small molecules can allosterically inhibit huPBGS activity by stabilizing the hexamer and putatively potentiate disease states. Two such inhibitors were identified by in silico docking to a hexamer‐specific surface cavity of huPBGS. The compounds were confirmed to inhibit wild‐type huPBGS activity by stabilizing the hexamer in vitro, and showed increased potency against two porphyria‐associated variants. One of the compounds is a structural analog to two amebicidal drugs, which have porphyria‐like side effects, and were found to stabilize the huPBGS hexamer in vitro. If the drugs can inhibit huPBGS by inducing hexamer formation in vivo, this would constitute an unprecedented explanation for a drug side effect. It is possible that other known drugs, toxins, or environmental contaminants could have a hexamer‐stabilizing inhibitory effect on huPBGS. An ongoing screen of ~1500 compounds approved for pharmaceutical use has so far revealed 6 compounds that stabilize the huPBGS hexamer in vitro.