David Sowa '12 and Sonam Lhaki '12
acetyltransferase that promotes transcription
of the histones, thereby undoing the nucleosome and exposing DNA
regions for transcription. The p300/CBP
protein consists of two
subdomains known as the N and C subdomains, with a portion of the C
containing a loop that caps both ends of the N domain. Another
feature of the structure is the presence of a tunnel and a pocket that
with lysine side chains, which leads to acetylation of these lysines in
through direct interaction with RNA polymerase
II and transcription
factors. Since p300/CBP
play important roles in
many biological processes, such as cell proliferation and
research is being undertaken to see how they function in cancer.
For example, research has
shown that p300/CBP may contribute to p53 degradation and therefore
resist apoptosis, which would therefore lead to cancer (4).
Because of the
mutant p300/CBP with
cancer, as well as its function in other diseases including cardiac
diabetes, inhibition of these proteins may represent an avenue for
In this tutorial, p300/CBP
is shown complexed with Lys-CoA, a conjugate of lysine and coenzyme A
specifically targets p300 and inhibits its histone acetylase function.
.p300 consists of two
as the C and the N subdomains. The C
the entire structure and caps
ends of the larger N
a loop that spans the
domain of p300 consists of
a central β-sheet
composed of seven
of the α-helices
and the last
the C subdomain.
p300 is shown binding the Lys-CoA substrate. Lys-CoA consists
lysine portion and a coenzyme A
portion, both of
which assist in association with p300.
acetylation activity (5).
interactions contribute to p300's effective binding to the substrate.
In one case, the
L1 loop of the N subdomain buries 266 Å2
of the lysine
portion of Lys-CoA and contributes
important interaction is a hydrogen bond formation
between the oxygen of p300's Trp1436
and a nitrogen
on the substrate's
aliphatic portion of the lysine interacts with a hydrophobic tunnel of
This tunnel is composed of residues Tyr1397,
the CoA portion of the inhibitor contributes to protein-inhibitor
include hydrogen bonds
and the Arg1410
residue of p300
of these bonds is a water-mediated
contact, but the water
study, it was found that an R1410C mutation
was a factor in human
lung cancer, probably due to the resulting reduction
HAT activity. This
study highlights the importance of the Arg
a shallow, electronegative groove
connects this substrate-binding
electronegative pocket that is also thought to effect efficient p300
activity. This pocket is formed by side-chains of the
main-chain residues Thr1357,
these residues diminishes HAT
activity, which indicates
that they must
support the protein-substrate interaction...
Comparison of p300 with Other HATs
some ways, p300/CBP is structurally similar to other HAT enzymes. There
is structural conservation
in the central core region associated with
acetyl-CoA cofactor binding (as is the case with the
p300, yeast Gcn5, and yeast Esa1 HAT domains).
Yet, there's plenty that sets p300 apart.
unique feature of the p300 HAT domain is that it has the unusually long
loop that interacts with the Lys-CoA inhibitor.
loop's position allows the protein to effectively bind the Lys-CoA
addition, the substrate-binding pockets of the p300 HAT domain are more
shallow and acidic. Gcn5 and Esa1, on the other hand, have deeper and
more apolar pockets. Comparison
Gcn5, and Esa1 electrostatic
reveals the greater negative character of the p300 HAT
domain. This leads to the selective binding of the basic (lysine)
portion of Lys-CoA.
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research has examined the potential role of
histone acetyltransferases in various diseases, including cancer,
asthma, COPD, and viral infections. Because
different types of histone acetyltransferases catalyze acetylation on
certain types of lysine residues, many HATs are now being considered as
targets for therapy (3). p300/CBP is being researched for these very
reasons--it may be a contributing factor in human cancers.
Currently, a challenge facing researchers is developing
small-molecule inhibitors of HATs that can
be used as potential
drugs. One example in the case of p300 is C646
, which was found to
competitively inhibit p300 moreso than it inhibited other
acetyltransferases. C646 is an intriguing potential drug because it
will normalize cell growth
even better than other
potent inhibitors (2).
Finally, other methods for inhibiting HATs that are being considered
include alteration of substrate specificity, targeting of specific
loci, restricting access of non-target proteins, and coordinating the
multiple enzyme activites of the complex (1). Only further research
will reveal if one of these is the key to treating cancer.
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(1) Berndsen, Christopher E.
and John M.
Denu. 2008. Catalysis and substrate selection by histone/protein lysine
acetyltransferases. Current Opinion
Structural Biology 18:682-689.
(2) Bowers, Erin M., Gai Yan, Chandrani
Mukherjee, Andrew Orry, Ling Wang, Marc A. Holbert, Nicholas T. Crump,
Catherine A. Hazzalin, Glen Liszczak, Hua Yan, Cecilia Larocca, S.
Adrian Saldanha, Ruben Abagyan, Yan Sun, David J. Meyers, Ronen
Marmorstein, Louis C. Mahadevan, Rhoda M. Alani, and Philip A. Cole.
2010. Virtual Ligand Screening of the p300/CBP Histone
acetyltransferase: Identification of a Selective Small
Molecule Inhibitor. Chemistry
Biology 17(5): 471-482.
Frank J. and Hidde J. Haisma.
2009. Histone acetyltransferases as emerging drug targets. Drug Discovery Today
(4) Goodman, Richard H.
2000.CBP/p300 in cell growth, transformation, and development. Genes & Dev
(5) Lau, Ontario D., Tapas
Raymond E. Soccio, Slimane Ait-Si-Ali, Ehab M. Khalil, Alex Vassilev,
Alan P. Wolffe, Toshihiro Nakatani, Robert G. Roeder, and Philip A.
Cole. 2000. HATs off: selective synthetic inhibitors of the histone
acetyltransferases p300 and PCAF. Molecular
X., Ling Wang, Kehao
Thompson, Yousang Hwang, Ronen Marmorstein, and Philip A. Cole. 2007.
The structural basis of protein acetylation by the p300/CBP
transcriptional coactivator. Nature
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