For
a better understanding of protein–inhibitor interactions,
we report structural, thermodynamic, and biological analyses of the
interactions between
S
-trityl-
l
-cysteine
(STLC) derivatives and the motor domain of kinesin spindle protein
Eg5. Binding of STLC-type inhibitors to Eg5 was enthalpically driven
and entropically unfavorable. The introduction of a
para
-methoxy substituent in one phenyl ring of STLC enhances its inhibitory
activity resulting from a larger enthalpy gain possibly due to the
increased shape complementarity. The substituent fits to a recess
in the binding pocket. To avoid steric hindrance, the substituted
STLC is nudged toward the side opposite to the recess, which enhances
the interaction of Eg5 with the remaining part of the inhibitor. Further
introduction of an ethylene linkage between two phenyl rings enhances
Eg5 inhibitory activity by reducing the loss of entropy in forming
the complex. This study provides valuable examples of enhancing protein–inhibitor
interactions without forming additional hydrogen bonds.
Oligopeptide permease A (OppA) plays an important role in the nutrition of cells and various signaling processes. In archaea, OppA is a major protein present in membrane vesicles of Thermococcales. Because there being no crystal structures of archaeal OppAs determined to date, we report the crystal structure of archaeal OppA from Thermococcus kodakaraensis (TkOppA) at 2.3 Å resolution by the single‐wavelength anomalous dispersion method. TkOppA consists of three domains similarly to bacterial OppAs, and the inserted regions not present in bacterial OppAs are at the periphery of the core region. An endogenous pentapeptide was bound in the pocket of domains I and III of TkOppA by hydrogen bonds of main‐chain atoms of the peptide and hydrophobic interactions. No hydrogen bonds of side‐chain atoms of the peptide were observed; thus, TkOppA may have low peptide selectivity but some preference for residues 2 and 3. TkOppA has a relatively large pocket and can bind a nonapeptide; therefore, it is suitable for the binding of large peptides similarly to OppAs of Gram‐positive bacteria.
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