 |
PDBsum entry 2wxl
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
The p110 delta structure: mechanisms for selectivity and potency of new pi(3)k inhibitors.
|
|
|
Authors
|
|
A.Berndt,
S.Miller,
O.Williams,
D.D.Le,
B.T.Houseman,
J.I.Pacold,
F.Gorrec,
W.C.Hon,
Y.Liu,
C.Rommel,
P.Gaillard,
T.Rückle,
M.K.Schwarz,
K.M.Shokat,
J.P.Shaw,
R.L.Williams.
|
|
|
Ref.
|
|
Nat Chem Biol, 2010,
6,
117-124.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been
implicated in numerous pathologies including cancer, diabetes, thrombosis,
rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive
PI(3)K inhibitors with a wide range of selectivities have entered clinical
development. In order to understand the mechanisms underlying the isoform
selectivity of these inhibitors, we developed a new expression strategy that
enabled us to determine to our knowledge the first crystal structure of the
catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme
in complex with a broad panel of isoform- and pan-selective class I PI(3)K
inhibitors reveal that selectivity toward p110 delta can be achieved by
exploiting its conformational flexibility and the sequence diversity of active
site residues that do not contact ATP. We have used these observations to
rationalize and synthesize highly selective inhibitors for p110 delta with
greatly improved potencies.
|
|
|
|
|
|
|
|
Figure 3.
(a–e) Shown are the binding modes of DL06 (a), DL07 (b),
ZSTK474 (c), AS5 (d) and GDC-0941 (e) in the active site of
p110δ. Met752 is in its 'in' position for all these compounds.
|
|
Figure 4.
(a) The highly p110δ-selective compound AS15 does not open
the specificity pocket and makes extensive use of a hydrophobic
patch between Trp760, Thr750 and Met752 adjacent to the
adenine-binding pocket. The 2mF[o] – DF[c] contouring level is
1σ. (b) Chemical structures of AS15 and PIK-39. (c)
Superposition of AS15 and PIK-39 to demonstrate their different
modes of binding within the active site of p110δ.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nat Chem Biol
(2010,
6,
117-124)
copyright 2010.
|
|
|
|
|
|
|
