Introduction 
2. Time-resolved images of events at the ac- 
tive site of an enzyme. New ways of using 
synchrotron x-ray radiation permit very rapid 
measurements of diffraction data, so that in prin- 
ciple it should be possible to follow the struc- 
tural changes that occur during an enzymatic re- 
action. If we understood these changes, it might 
be possible to develop enzymes with usefully al- 
tered properties and to synthesize enzyme inhibi- 
tors with enhanced specificity. 
3. The role of molecular recognition in the 
regulation of cellular activity. How do proteins 
that control transcription recognize specific DNA 
sequences? How do cell surface proteins in the 
immune system recognize and present antigens? 
The answers to these questions are beginning 
to emerge from crystal structures of molecular 
complexes, such as the complexes formed by reg- 
ulatory proteins with DNA, those formed by bind- 
ing proteins with their appropriate ligands, of an- 
tibodies with antigens, and of MHC molecules 
with peptides. These current efforts give consid- 
erable promise for understanding how hormones 
or neurotransmitters trigger a cascade of events 
that involves the formation and dissociation of 
protein assemblies inside cells. A large and medi- 
cally significant class of regulatory interactions 
involves the protein products of oncogenes or 
proto-oncogenes . 
As our knowledge of important proteins rap- 
idly increases, we can only hope that our capacity 
to anticipate aspects of structures not yet deter- 
mined will keep pace. The goal of accurately pre- 
dicting the three-dimensional structure of any 
protein from its amino acid sequence is still a 
long way off. But recent advances in computa- 
tional chemistry make it possible to predict the 
effects of small perturbations, such as point mu- 
tations, on the folding of a protein and to calcu- 
late differences in binding free energies for re- 
Investigators in the Structural Biology Program 
Agard, David A., Ph.D. 
Briinger, Axel T., Ph.D. 
Burley, Stephen K., M.D., D.Phil. 
Deisenhofer, fohann, Ph.D. 
Fox, Robert O., Ph.D. 
Harrison, Stephen C, Ph.D. 
Hendrickson, Wayne A., Ph.D. 
Kuriyan, John, Ph.D. 
lated ligands. And systematic approaches to 
designing drugs, such as antagonists or inhibitors 
of enzymes, are beginning to emerge now that we 
can carry out meaningful calculations on known 
structures. 
Nuclear magnetic resonance (NMR) meth- 
ods offer an alternative route to determining the 
three-dimensional structures of peptides and 
small proteins. The DNA-binding domains of tran- 
scriptional activators and repressors are good 
candidates for this type of analysis. The past two 
years have seen the determination by NMR of the 
structure of a developmentally important DNA 
sequence known as a homeodomain and of a 
DNA-binding structure known as a zinc finger. 
NMR has the great advantage that it circumvents 
the need to crystallize the protein to be studied. 
At the other end of the size scale, imaginative 
combinations of light and electron microscopy 
have begun to reveal important patterns and re- 
gularities in very large structures, such as chro- 
mosomes, viruses, and receptors. New methods 
for recording images and enhancing contrast in 
light microscopy make it possible to record in 
real time the events of intracellular transport or 
the process of chromosome condensation. As the 
molecules that generate these large-scale intra- 
cellular motions are characterized, it should be- 
come possible to relate such changes to the spe- 
cific molecular recognition events that control 
them. It is fortunate, but not coincidental, that as 
biologists have become increasingly aware of the 
need to know the precise structure of the mole- 
cules that mediate the phenomena they are inter- 
ested in, a whole range of new experimental 
methods has been developed, and a new genera- 
tion of structural biologists has emerged to assist 
them and to advance their understanding of the 
complex relationships between structure and 
function. 
Matthews, Brian W., Ph.D., D.Sc. 
Pabo, Carl O., Ph.D. 
Quiocho, Florante A., Ph.D. 
Sedat,John W., Ph.D. 
Sigler, Paul B., M.D., Ph.D. 
Sprang, Stephen R., Ph.D. 
Steitz, Thomas A., Ph.D. 
Wiley, Don C, Ph.D. 
W. Maxwell Cowan, M.D., Ph.D. 
Vice President and Chief Scientific Officer 
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