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P‐glycoprotein models of the apo and ATP‐bound states based on homology with Sav1866 and MalK
Author(s) -
O'Mara Megan L.,
Tieleman D. Peter
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.07.069
Subject(s) - chemistry , homology modeling , glycoprotein , biochemistry , homology (biology) , nucleotide , transmembrane domain , protein structure , cysteine , amino acid , gene , enzyme
We exploit the biochemical and sequence similarity between Staphylococcus aureus Sav1866 and P‐glycoprotein to develop a homology model of P‐glycoprotein representing an ATP‐bound state, which captures the major features of the low‐resolution EM structure and is consistent with cysteine mutagenesis studies. Using insights from the MalK crystal structures and BtuCD simulations, we model two nucleotide‐free conformations. Conformational changes are characterized by pincering rigid‐body rotations of the nucleotide‐binding domains, inducing transmembrane domain reorganizations which correspond to the two lowest frequency normal modes of the protein. These conformations (see supplementary material) may characterize some of the major steps in the nucleotide catalytic cycle.