By solving the 3-D structure of one particular enzyme
that controls genes, researchers at
Johns Hopkins, working with colleagues at the University of
Pennsylvania and the Wistar Institute,
have discovered how the enzyme adds chemical groups to
chromosomes to alter gene function. The
research team reported in the Feb. 14 issue of
Nature that the new structure paves the way for
developing new chemical inhibitors and therapies for
diseases like cancer.
"We've had a chemical inhibitor of p300 for about nine
years now, but without the structure, we
had no idea how it was working or, more importantly, how to
improve on it," said Philip Cole, professor
and director of Pharmacology and Molecular Sciences at
Johns Hopkins.
The enzyme p300/CBP adds chemical acetyl groups to
chromosomes, a process that generally
turns genes on. "Some cancers like melanoma appear to be
driven by acetylation," Cole said. Inhibiting
such enzymes might be useful anti-cancer therapies and for
other diseases such as diabetes and heart
disease.
To figure out the structure of p300/CBP, the
researchers overcame obstacles using a number
of technical tricks developed over seven years to
crystallize the enzyme in the presence of a chemical
known to inhibit its activity. The team then used X-rays to
determine the structure of the purified
protein-inhibitor crystals. Using computers, they then
assembled a 3-D model of p300/CBP.
The enzyme p300/CBP is one of several enzymes--histone
acetyltransferases, or HATs--that
can put acetyl groups onto chromosomes. But the other
enzymes don't share similar building block
patterns with p300/CBP, according to Cole. However, once
the researchers had the structure, they
were able to compare it with the structure of other enzymes
and found that the central region of the
enzyme, the part that holds the acetyl, has a shape similar
to that of other HATs.
The structure also revealed that p300/CBP puts acetyl
groups onto chromosomes by a so-called
hit-and-run mechanism. Whereas other enzymes hold onto both
the acetyl and the chromosome at the
same time and encourage the chemical transfer, p300/CBP
holds onto the acetyl and transfers the
acetyl to the chromosome without lingering or hanging
on.
"The structure shows that p300 has a tunnel that
allows the chromosome to bang into it and
leave," Cole said.
The team plans to follow up with enzyme studies to try
to develop improved chemical inhibitors
for p300/CBP. "We're still in our infancy of understanding
how to go after cancer," Cole said. "But this
definitely is a step in the right direction."
The research was funded by the National Institutes of
Health, FAMRI and the Kauf-man and
Keck foundations.
Authors on the paper are Ling Wang, Paul Thompson,
Yousang Hwang and Cole, all of Johns
Hopkins; and Xin Liu, Kehao Zhao and Ronen Marmorstein, all
of the Wistar Institute.
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