Importance of knowing tertiary structure

Bob Phair rphair at
Tue Jul 15 17:22:05 EST 1997

In my experience, the holy grail of being able to measure or calculate
the tertiary structure of a protein, is only holy to the extent that
this knowledge assists in identifying or modifying the *function* of the
protein under study. 

Your interesting post goes to the heart of the "structure-function"
paradigm. That paradigm rests on the theory (belief, hope, wish) that
function can be deduced from a detailed knowledge of structure. In some
cases, beautiful stories have emerged from this approach. In other cases
(e.g. CFTR) we know a huge amount about a gene and the protein for which
it codes, but we cannot even figure out why a failure of this protein
leads to cystic fibrosis, much less provide a cure. The "hot" field of
rational drug design, is another example of this paradigm in action. The
central idea of this field is that if you know the structure of a target
protein (enzyme, transporter, etc.), you should be able to design a
molecule that fits perfectly into its active site, or perfectly into an
allosteric binding site, and thus control the target's function.
Millions of dollars have been invested in this approach. My impression
is that you would be hard pressed to find major successes.

Some investigators feel the structure-function paradigm has been
oversold. These doubters would suggest that it's more efficient and more
effective to study function directly, but this is not one of those
questions that should be prejudged. As scientists, we all "place our
bets" on a subset of the possible experimental and theoretical
approaches to a given problem. Some of us will be wrong, others right.
That's what makes science work. It's also, in large measure, why we find
it exhilirating.

Robert D. Phair, Ph.D.  rphair at
BioInformatics Services
Partnering and Outsourcing for Computational Biology

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