Dr. Steitz is also Professor of Molecular Biophys- 
ics and Biochemistry and of Chemistry at Yale 
University. 
Articles 
Kohlstaedt, L.A., Wang, J., Friedman, J.M., Rice, 
P.A., and Steitz, T.A. 1992. Crystal structure at 
3 5 A resolution of HIV-1 reverse transcriptase 
complexed with an inhibitor. Science 256: 1 783- 
1790. 
Schultz, S.C., Shields, G.C., and Steitz, T.A. 1991 . 
Crystal structure of a CAP-DNA complex: the DNA 
is bent by 90°. Science 253:1001-1007. 
Story, R.M., and Steitz, T.A. 1992. Structure of the 
recA protein-ADP complex. Nature 355:374- 
376. 
Story, R.M., Weber, I.T., and Steitz, T.A. 1992. The 
structure of the E. coli recA protein monomer and 
polymer. Nature 355:318-325. 
STRUCTURAL MOLECULAR BIOLOGY 
Don C. Wiley, Ph.D., Investigator 
Class I histocompatibility glycoproteins carry 
short peptides derived from the cytoplasm of cells 
to the cell surface and present them to the surveil- 
lance of cytotoxic T lymphocytes (CTLs), which 
possess clonally distributed, hypervariable receptor 
molecules. CTLs specific for peptides derived from 
the organism's own proteins are eliminated or 
turned off by regulatory mechanisms. Thus if a CTL 
recognizes a histocompatibility glycoprotein- 
peptide complex on a cell surface, it is a signal that 
foreign peptides are being expressed in the cell 
such as would occur in a viral infection, and the CTL 
responds by killing the infected cell. 
For their biological function, class 1 molecules 
must be able to bind peptides of many different se- 
quences and to hold them very tightly. The binding 
must be essentially irreversible, so that peptide re- 
mains bound at the cell surface where the concen- 
tration of free peptide is near zero. In the past year. 
Dr. Wiley and his colleagues have determined and 
refined three class 1 structures to 2. 1-, 2.8-, and 1 .9- 
A resolution and may have discovered the key to the 
unusually tight peptide binding. 
The structure of HLA-B27 at 2.1-A resolution 
(with Drs. Joan Gorga and Jack Strominger) demon- 
strated that the collection of endogenous (self) pep- 
tides bound to HLA (human leukocyte-associated 
antigens) in the crystal were predominately 9-mer 
with arginine at peptide position 2 (P2). Further- 
more, the vast majority of the peptides bound with 
the same extended, kinked conformation, burying 
their amino and carboxyl termini in sites composed 
of residues conserved in all class 1 protein 
sequences. 
The complex of a single-peptide antigen from in- 
fluenza virus with the class 1 allele HLA-Aw68 was 
formed by in vitro reconstitution and its structure 
determined to 2.8 A. The conformation of this single 
viral peptide bound to H1A-Aw68 is remarkably simi- 
lar to that of the collection of endogenous peptides 
bound to HLA-B27, arguing that the mechanism of 
binding is general. The peptide is bound by its ends 
stretched out so that the sequence of most of the 
central residues can be read by the T cell receptor. 
The structure of HLA-Aw68 complexed with the 
collection of endogenous peptides was refined to 
1.9-A resolution. Surprisingly, electron density for 
only the first three and last two peptide residues was 
visible. Peptide elution and sequence experiments 
indicate that peptides of various length, from 8-mer 
to 11-mer, bind tightly to HIA-Aw68, confirming 
the crystallographic interpretation that the center 
part of the peptide must bulge out of the site to 
varying degrees depending on peptide length. 
These data together argue that the key to tight, 
essentially irreversible binding is fitting the amino 
and carboxyl termini into the conserved binding 
sites. Polymorphic residues in the binding sites de- 
termine which peptide sequences can fit their ends 
into the termini binding sites. Extensive hydrogen- 
bonding networks in both terminal sites would ap- 
pear not only to hold the peptide but also to explain 
the peptide-dependent stability of the histocompati- 
bility molecule's structure. 
Dr. Wiley and his co-workers are currently refin- 
ing a model of the human class II histocompatibility 
glycoprotein HIA-DRl complexed with a collection 
of endogenous peptides. A crystal with a single influ- 
enza peptide has also been prepared, and diffraction 
data have been collected with synchrotron radia- 
tion, to at least 2.8-A resolution. A complex of DRl 
with the superantigen SEB is also being built at high 
490 
