|
Figure 4.
Figure 4 Superposition of the active sites of three complexes of
calf spleen PNP with various inhibitors: (i) the binary complex
with the multisubstrate analogue inhibitor DFPP-G (cpk colours,
present structure; PDB code [254]1v48 ), (ii) the binary complex
with the multisubstrate analogue inhibitor (S)-PMPDAP (magenta;
PDB code [255]1lv8 , monomer A; Bzowska et al., 2004[256]
[Bzowska, A., Koellner, G., Wielgus-Kutrowska, B., Stroh, A.,
Raszewski, G., Holý, A., Steiner, T. & Frank, J. (2004).
Submitted.]-[257][bluearr.gif] ) and (iii) the ternary complex
with the transition-state inhibitor immucillin G and phosphate
(green; PDB code [258]1b8n ; Kicska et al., 2002[259] [Kicska,
G. A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Schramm, V.
L. & Kim, K. (2002). J. Biol. Chem. 277,
3226-3231.]-[260][bluearr.gif] ). Active-site amino acids that
form putative hydrogen bonds with the inhibitors are included
(see also Fig. 2[261] [link]-[262][turqarr.gif] ). In addition,
the location of Phe200 involved in [263][pi] -stacking
interaction with the inhibitor base is also shown (thin lines).
Phosphate and phosphonate groups of the multisubstrate analogue
inhibitors [DFPP-G and (S)-PMPDAP] and orthophosphate in the
ternary complex with immucillin G occupy the same position in
all three structures. The side chain of Arg84 in the complex
with (S)-PMPDAP (drawn in light magenta) is directed away from
the phosphate-binding site and does not form hydrogen bonds with
the phosphonate group of the inhibitor. Tyr88, Met219 and His257
only form direct hydrogen-bonding contacts in the complex with
immucillin G. The inhibition potency of the three inhibitors
shown in the figure spans almost six orders of magnitude: from
30 pM for immucillin G to 6 µM for (S)-PMPDAP (see text for
details). The number of direct hydrogen-bonding contacts formed
by these three ligands correlates well with their inhibition
potency as observed in solution.
|
