PROGRAM IN STRUCTURAL BIOLOGY 
The Institute's Program in Structural Biology 
is its newest, begun in 1986, with the primary goal 
of understanding in atomic detail the three- 
dimensional architecture of proteins, protein assem- 
blies, and the complexes formed by proteins that 
interact with RNA and DNA. This structural informa- 
tion is being explored to determine how these mole- 
cules fold and assume their active configurations 
and how they interact with each other. Computa- 
tional tools are also under development to aid in 
structure determination. 
Investigators in the structural biology program 
are located at Harvard University, the Massachusetts 
Institute of Technology, Rockefeller University, the 
University of Texas Southwestern Medical Center at 
Dallas, the University of Oregon at Eugene, Baylor 
College of Medicine, Yale University, Columbia Uni- 
versity College of Physicians and Surgeons, and the 
University of California at San Francisco. The Insti- 
tute is also developing a synchrotron resource for 
use by its investigators and the larger biomedical 
community at the National Synchrotron Light Source 
at Brookhaven National Laboratory on Long Island. 
Assistant Investigator Axel T. Briinger, Ph.D. (Yale 
University) and his colleagues focus their research 
at the interface between theory and experiment in 
the area of structural biophysics. A major effort 
centers on assessing and improving the accuracy of 
three-dimensional structures of biological macro- 
molecules based on x-ray crystallography and nu- 
clear magnetic resonance spectroscopy. During the 
past year novel criteria have been developed that 
show promise in detecting errors and that could 
prevent researchers from overfitting the experimen- 
tal data. Another focus of Dr. Briinger's research is 
the simulation of macromolecular interactions and 
energetics. Prediction of the geometry of helical su- 
percoils was quite successful in the case of the di- 
merization region of the GCN4 transcriptional acti- 
vator protein. The method has also been applied to 
predict the structure of the glycophorin-A trans- 
membrane domain. 
The work of Investigator Wayne A. Hendrickson, 
Ph.D. (Columbia University) and his colleagues in- 
tegrates structural studies of significant biological 
molecules with the development of methods to facil- 
itate these investigations. The major biological 
themes at present include cell surface interactions, 
genetic replication, carbohydrate recognition, and 
oxygen transport. Their research on methods fo- 
cuses on synchrotron radiation, crystallographic 
phase evaluation from multiwavelength anomalous 
diffraction (MAD) measurements, crystallographic 
refinement, and computational crystallography. 
During the past year the refined structures of 
the carbohydrate recognition domain (CRD) from 
mannose-binding proteins, both unligated and com- 
plexed with a high-mannose oligosaccharide, have 
been used to define the characteristics of sugar bind- 
ing and selectivity in this system. Other new struc- 
tures include the T cell co-receptor CDS and an ad- 
hesive type III fibronectin domain from the 
extracellular matrix protein tenascin. 
Structural studies of simple viruses and soluble 
receptor fragments have revealed important aspects 
of assembly and recognition. Further progress with 
more complex structures in the laboratory of Inves- 
tigator Stephen C. Harrison, Ph.D. (Harvard Univer- 
sity) will build on technical advances made during 
the past year in working on crystals of SV40 (simian 
virus 40), rotavirus single-shelled particles, and 
transferrin receptor. New structures of the DNA- 
binding elements from two yeast transcriptional 
activators — GAL4 and GCN4 — reveal the organiza- 
tion of recognition modules not previously seen at 
high resolution. The significance of flexible seg- 
ments is evident in both cases. 
The laboratory of Investigator Don C. Wiley, 
Ph.D. (Harvard University) continues to study the 
structure and function of cellular and viral surface 
molecules. In the past year the laboratory deter- 
mined the structure of a complex between an influ- 
enza virus protein and a component of its cellular 
receptor. This opens the way to designing drugs that 
would inhibit virus from binding to cells. Using re- 
combinant DNA methods, the laboratory has also 
studied the membrane fusion mechanism by which 
viruses enter cells. In other studies the three- 
dimensional structure was determined for the hu- 
man histocompatibility antigen, a protein found on 
all human cells. The function of this protein during 
the immune response to viral infections and in the 
rejection of tissue transplantation is now under 
study. 
Investigator Brian W. Matthews, Ph.D., D.Sc. (Uni- 
versity of Oregon) and his co-workers use x-ray crys- 
tallography, in concert with genetic, thermody- 
namic, and other techniques, to address some of the 
fundamental problems in biology: How do proteins 
spontaneously fold into their biologically active 
three-dimensional configurations? What determines 
the stability of these folded proteins? Can stability 
be improved? How do proteins interact with each 
other? How do proteins interact with DNA? How do 
STRUCTURAL BIOLOGY 457 
