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Crystal structure of a gene regulator identified
By Bijal P. Trivedi

Scientists have determined the structure of an enzyme that plays a critical role in turning genes on and off. The enzyme, Esa1, is essential for regulating genes in yeast, and scientists believe its counterparts in humans, implicated in certain types of leukemia and in HIV infection, may have a similar structure and might function in the same way. The structure is expected to shed light on the physical and molecular changes that are required to switch on a gene. It will also be a valuable tool for drug design.

A ribbon diagram shows the 3-D Esa1 protein (blue) crystallized in a molecular embrace with coenzyme-A (red) which provides the acetyl molecule required to alter the histone.

In the cell, DNA is wound around large globular proteins called histones, like cotton around a reel. When the DNA is wrapped around the histone, the genes on that stretch of DNA remain inactive. "Esa1 chemically alters the histone, which then loosens its grip on the DNA and allows the genes to be read or switched on," says Shelley Berger, of the Wistar Institute in Philadelphia, Pennsylvania.

Esa1 is a member of the HAT (histone acetyltransferase) family of proteins that modify the histones by attaching an acetyl molecule; the chemical change that is believed to loosen the DNA and make the genes accessible to the gene reading machinery in the cell. The human proteins TIP60, which interacts with HIV proteins, and MOZ, which is involved in certain leukemias, are also HAT proteins. But while the Esa1 and TIP60 look like obvious counterparts sharing a similar sequence of amino acids, MOZ does not appear to be related.

When Berger and her colleague, Ronen Marmorstein, determined the structure of Esa1 they were surprised to find that there were structural similarities to MOZ and other HAT proteins. "HAT proteins can look pretty different at the genetic level. You could never predict the structural similarities among these proteins from just reading the gene sequence," says Berger.

It is a possibility that certain cancers arise because a HAT protein is misbehaving, and turning on genes at the wrong time, says Berger. Knowing which part of a HAT protein handles the histone will help scientists to design drugs that can block this action.

Esa1's structure was determined using X-ray crystallography. Esa1 was first crystallized and then bombarded with x-rays that bounce off and produce a pattern of dots on photographic plates. The arrangement of the dots is used to construct a 3-dimensional model of the protein.

Understanding how genes are switched on and off is critical to understanding disease and the development of every organism.

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Yan, Y. et al. Crystal structure of yeast Esa1 suggest a unified mechanism for catalysis and substrate binding by histone acetyltransferases. Molecular Cell 6, 1195-1205 (November 2000).

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