1P145 Crystal structure of the N-domain of human cardiac troponin C in complex with trifluoperazine

Abstract

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Crystal Structure of Cardiac Troponin C Regulatory Domain in Complex with Cadmium and Deoxycholic Acid Reveals Novel Conformation

“…The ligands and backbone conformation of the loop is virtually identical to the Ca 2+ coordination by EF 2 in other cTnC structures. The backbone of the coordinating loop region (Asp65-Glu76) aligns with a root-mean-square deviation (r.m.s.d) of 0.4 Å with 1J1E 22 0.3 Å with 1WRK 23 . The similarity of calcium and cadmium coordination has previously been corroborated by other calcium binding proteins such as calbindin D9k that displays comparable coordination of Cd 2+ in solution to that of Ca 2+ 24 .…”

“…The DXC molecule has similar features to the Ca 2+ sensitizing drugs such as trifluoroperzaine (TFP) 23 , EMD 57033 31 , and levosimendan 32 . They each have at least two hydrophobic fused rings and a hydrophilic head group.…”

“…The overall conformation of cNTnC is very similar in all of these structures. They include the NMR structure of cNTnC in complex with a bepridil molecule and the cTnI 147-163 switch peptide (PDB: 1LX) 35 , the NMR structure of cNTnC in complex with a W7 molecule (PDB: 2KFX) 36 and with both a W7 molecule and the cTnI 147-163 switch peptide (PDB: 2KRD) 39 , the NMR structure of cNTnC in complex with the cTnI 147-163 switch peptide and the analog of levosimendan, 2’,4’-difluorobiphenyl-4-yloxy acetic acid (dfbp-o) (PDB: 2L1R) 37 , and the crystal structure of cNTnC in complex with trifluoperazine (PDB: 1WRK) 23 . Using the best representative chain from each NMR ensemble and the single chain from 1WRK model, the superimposition of all the above mentioned structures yields a C α r.m.s.d of 2.3 Å, indicating their similar overall conformation.…”