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Figure 3.
HdmX and Hdm2 have important differences in the Leu and Trp
pockets. A, superposition of the complexes HdmX-compound 1
(color coding is as in Figs. 1A and 2, i.e. HdmX with carbons
are in yellow, compound 1 with carbons are in cyan) and
Hdm2-optimized p53 peptide (PDB entry code 1T4F; Hdm2 and ligand
with carbons in white) zoomed in on the Leu and Trp pockets.
Amino acid residues that differ in identity between HdmX and
Hdm2 have two labels (upper label from Hdm2), otherwise only one
label (numbering for HdmX). The differences Pro^95 versus
His^96, Met^53 versus Leu^54, and Leu^98 versus Ile^99 for HdmX
versus Hdm2 modify the shape of the Leu pocket. In particular,
the presence and position of CB-Pro^95 for HdmX leads to a
different position of the Leu side chain from the ligand. B,
superposition of the complexes HdmX-compound 2 (color coding as
in Fig. 2, i.e. HdmX with carbons in brown, compound 2 with
carbons in magenta) and Hdm2-compound 2 (PDB entry code 2GV2;
Hdm2 and ligand with carbons in white), zoomed in on the Leu and
Trp pockets. The presence of a 6-chlorine substituent at the
bottom of the Trp pocket leads to dramatic side chain movements
of Leu^98, Tyr^99, and Pro^95 for HdmX, where as Hdm2 shows
practically no changes (cf. Figs. 2 and 3A). The Leu side chain
of compound 2 can now adopt a very similar position for the HdmX
and Hdm2 complexes (because the Leu pocket has been widened for
HdmX), in contrast to the situation with a 6-H substituent in
the Trp pocket (Fig. 3A). C, same superposition as in Fig. 3B
but zoomed in on the Trp pocket. The differences Leu^85 versus
Phe^86 and Leu^98 versus Ile^99 for HdmX versus Hdm2 modify the
shape of the Trp pocket. In particular, the bottom of the Trp
pocket is not yet completely filled by the 6-chlorine for HdmX.
The important van der Waals interactions made by the 6-chlorine
with Phe^86 for Hdm2 are only partially substituted by
hydrophobic interactions with Leu^98 for HdmX. The diagram is
programmed for stereo viewing.
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