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HWI Scientist Dr. Dan Gewirth's
Groundbreaking Research Makes Cover of Molecular Cell.
Image � by Dan Gewirth |
Since 2001, Gewirth and his lab have been
using the technique of X-ray diffraction to solve the first
high-resolution structure of this protein from mammalian origins, to
understand its function and to determine if it is indeed a member of
the HSP90 family of proteins. The structure and activity patterns of
this protein prove conclusively that this is indeed a member of the
same family.
�Our work opens the door to a more intensive evaluation of this
protein both from a mechanistic as well as a therapeutic point of view.
In addition to aiding our understanding of the fundamental biology of
chaperone-mediated protein folding, this work lays the foundation for
the design of drugs that specifically target individual members of the
hsp90 family� Gewirth, who also holds a post as an associate professor
in the Structural Biology department of the University at Buffalo
which is housed at the Hauptman-Woodward Medical Research Institute,
said.
Why Is This Important?
This is groundbreaking work for a number of reasons: It is the first
high resolution picture of any member of the hsp90 family. High
resolution is needed for a detailed understanding of protein function.
It is also the first structure of a mammalian member of the hsp90
family. This is important since drugs and other therapeutics need to
be developed for human use, and thus must target the mammalian protein.
Finally, the work shows for the first time how members of the hsp90
family of chaperone proteins can differ from each other, while still
being part of the same overall family.
Scientific Understanding
The mammalian member of this protein family is different than those
previously studied which were solved from either bacteria or yeast.
Human energy production and consumption rates are more similar to
those found in the GRP94 proteins than to the more widely studied
HSP90 proteins. This means that the insights gained by a greater
scientific understanding of how GRP94 works will have more direct
applications to human diseases.
Medical Implications and Drug Development
Inhibitors currently are being designed for HSP90 in an attempt to
treat the diseases in which HSP90 plays a role. However, these are
broad-spectrum inhibitors of all HSP90s which means that unwanted side
effects may occur. The Gewirth lab�s work clarifies GRP94�s place in
this family and has already stimulated interest in this chaperone as a
drug target. This understanding would allow for the long-term
development of a family of drugs that could be narrowly targeted for
individual proteins, for example specifically treating sepsis only.
Economic Impact
Just as companies have been founded to develop HSP90 inhibitors, the
same potential exists here. �This will spur a new line of inquiry into
GRP94. While this work is its infancy, medicinal chemists will be
interested in developing GRP94-targeted drugs,� Gewirth said.
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