group as well as the ring system of the tyrosine. 
These structures have set the stage for modeling the 
structure of other SH2 domains and for designing 
mutations and inhibitors that affect SH2 function. 
The laboratory is also continuing work on redox 
enzymes, with funding from the National Institutes 
of Health. Thioredoxin and proteins closely related 
to it (protein disulfide isomerases) have been impli- 
cated in the process by which disulfide-containing 
proteins fold up rapidly without scrambling their 
disulfide pairings. Drs. James Bardwell, Karen 
McGovern, and Jon Beckwith (Harvard Medical 
School) have recently identified an E. coli protein 
that is required for the correct folding of disulfide- 
containing proteins in vivo. This 21-kDa protein, 
the product of the dsbA gene, has no significant se- 
quence similarity to any protein of known three- 
dimensional structure, except for a short stretch of 
amino acids related to the active site of thioredoxin 
(including the redox-active disulfide bond) . 
Knowledge of the three-dimensional structure of 
the protein will aid in understanding its mechanism 
of action and will reveal whether dsbA belongs to 
the thioredoxin family. The protein has been puri- 
fied in the laboratory, and single crystals that dif- 
fract to 2 -A resolution have been obtained. A variant 
dsbA that contains selenomethione instead of methi- 
one has been produced and crystallized. This will 
allow the application of the multiwavelength x-ray 
phasing technique for the determination of the 
structure. 
Dr. Kuriyan is also Associate Professor and Co- 
Head of the Laboratory of Molecular Biophysics at 
the Rockefeller University. 
Books and Chapters of Books 
Williams, C.H., Jr., Prongay, A.J., Lennon, B.W., and 
Kuriyan, J. 1991- Pyridine nucleotide-disulfide 
oxidoreductases: overview of the family and some 
properties of thioredoxin reductase altered by 
site directed mutagenesis: C135S and C138S. In 
Flavins and Flavoproteins (Curti, B., Zannetti, 
G., and Ronchi, S., Eds.). Berlin: Walter de 
Gruyter, pp 497-504. 
Articles 
Henderson, G.B., Murgolo, N.J., Kuriyan, J., Osa- 
pay, K., Kominos, D., Berry, A., Scrutton, N.S., 
Hinchclifife, N.W., Perham, R.N., and Cerami, A. 
1991. Engineering the substrate specificity of glu- 
tathione reductase toward that of trypanothione 
reduction. Proc Natl Acad Sci USA 88:8769- 
8773. 
Kong, X.-P., Onrust, R., O'Donnell, M., and 
Kuriyan, J. 1992. Three-dimensional structure 
of the i8 subunit of E. coli DNA polymerase III 
holoenzyme: a sliding DNA clamp. Cell 69:425- 
437. 
Kuriyan, J., Kong, X. P., Krishna, T.S.R., Sweet, 
R.M., Murgolo, N.J., Field, H., Cerami, A., and 
Henderson, G.B. 1991 . X-ray structure of trypan- 
othione reductase from Crithidia fasciculata at 
2.4-A resolution. Proc Natl Acad Sci USA 
88:8764-8768. 
Waksman, G., Kominos, D., Robertson, S.C., Pant, 
N., Baltimore, D., Birge, R.B., Cowburn, D., Hana- 
fusa, H., Mayer, B.J., Overduin, M., Resh, M.D., 
Rios, C.B., Silverman, L., and Kuriyan, J. 1992. 
Crystal structure of the phosphotyrosine recogni- 
tion domain SH2 of \-src complexed with 
tyrosine-phosphorylated peptides. Nature 358: 
646-653. 
STRUCTURAL BASIS OF INTERACTIONS WITHIN AND BETWEEN MACROMOLECULES 
Brian W. Matthews, Ph.D., D.Sc, Investigator 
Dr. Matthews and his colleagues use x-ray crystal- 
lography, in concert with other techniques, to ad- 
dress some fundamental problems in biology: How 
do proteins spontaneously fold into their biologi- 
cally 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 enzymes act as catalysts? 
The Protein-folding Problem 
An area of long-standing interest is the so-called 
protein-folding problem. How does a newly synthe- 
sized, extended peptide chain "know" how to fold 
spontaneously into its active three-dimensional 
shape? 
Although it has long been recognized that the 
amino acid sequence of a protein determines its 
three-dimensional structure, recent work from sev- 
STRUCTURAL BIOLOGY 477 
