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OVERLAY INDEPENDENT COMPARISON OF ACETYLCHOLINESTERASE 3D STRUCTURES REVEALS LIGAND SPECIFIC BACKBONE CHANGES UPON REVERSIBLE AND COVALENT BINDING
Author(s) -
RADIC ZORAN,
Rohrer Jacqueline,
Sidhom Morgana,
Han Jingting
Publication year - 2016
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.30.1_supplement.833.9
Subject(s) - chemistry , crystallography , protein data bank (rcsb pdb) , acetylcholinesterase , covalent bond , ligand (biochemistry) , conformational change , protein structure , stereochemistry , biochemistry , enzyme , receptor , organic chemistry
We developed a simple overlay independent comparison of protein 3D structure alpha carbon backbones and applied it to PDB deposited structures of acetylcholinesterase (AChE; EC 3.1.1.7) in order to identify backbone domains amenable to ligand binding associated conformational flexibility. Distance of each alpha carbon in the structure to a frame of reference point was determined first. We then calculated differences in corresponding distances between two different PDB structures and plotted as a function of amino acid number, or color coded and mapped onto ribbon or surface representation of an AChE structure. To reduce the influence of crystal packing we averaged corresponding distances determined in individual chains of crystallographic dimers before comparing different structures. We were able to observe systematic, previously undetected, conformational changes upon binding of tight and weak reversible ligands as well as covalent conjugates, phosphonylated and aged. Analogous structures of AChE from different species, human mouse and fish were compared revealing consistent conformational changes. Finally, our simplified comparative 3D structure analysis was contrasted to the sophisticated error‐scaled difference distance matrix analysis. Modest to moderate fluctuations of AChE backbone conformation upon complex or adduct formation may remain undetected in classical overlay analysis. Small, but systematic conformational changes in protein structures determined at low, 100 K temperature conditions, may prove as an important indicator of larger conformational changes at physiological conditions relevant for structure based design of modern therapeutics.