Fig 2aExactly twenty years ago, the structure of HLA-A2 was published: 8 October, 1987.1

That was actually the year before I started grad school, so I didn’t actually know a thing about it at the time, but it was the subject of one of the first journal club presentations I went to, maybe a year after it was published — so it was still fresh and surprising. What a jaw-dropping way to start my new career! I was already interested in MHC, but this was the hook.

At the time, some of the function of MHC class I had been worked out (first by by Doherty and Zinkernagel, and then lots of others) but the mechanisms were still pretty obscure. In particular, although it was known that adding peptide fragments to a cell could sensitize it to killing by cytotoxic T lymphocytes, it was by no means clear how that worked — it was still not known that peptides could physically associated with MHC class I. This was known for MHC class II, but it was not at all appreciated how similar in structure class I and II are — nor was it known how or where peptides bound to class II. However, the connection had been made: “By analogy, it is likely that the homologous class I molecules bind antigenic peptides, and that the HLA-peptide complex is recognized by T-cell receptors in CTL.2

Paper 1

At the time, crystallography was (at least in immunology) a fairly obscure, esoteric technique — mildly interesting, but not what you’d call practical, in terms of answering questions. 3 All that changed with this picture:


(Funny, I remember that picture as being, like, the size of a movie poster — in fact it’s the bottom part of one small corner of a single page. I can’t remember if it was on the cover of that issue of Nature, and the on-line archives don’t seem to have cover illustration that far back.)

That figure shows a little bit of undefined, unresolved mist (in pink) in the middle of the reasonably well-defined HLA-A2 molecule. The location of that little bit of mist, and its very mistiness, were the stunning part of the paper.

Of course, the location represents what we now call the peptide binding groove. (They had offered a drawing of the groove in Fig 2a [reproduced at the top of this post], but it didn’t click with me until I saw the later figure with the mist in it — then I went back and looked again!) 4 It offered a beautiful, clear, simple way to understand MHC function, a perfect dock for a peptide. At the time I had no idea that proteins could actually be so, well, physical — I had vague ideas of interactions and van der Waals forces and fancier stuff that held them together, it had never occurred to me that proteins were shaped like little Legoâ„¢ bricks, that could SNAP together with a satisfying CLICK. Here was something I could practically feel, pick up and move around, and it all made macroscopic sense. I think that I was not the only one who had the same reaction to the structure, too — this was the paper that led to a breakthrough in the use of structural information in immunology.

The even more exciting part was that the mist was mist. Even though the rest of the protein was clear,5 the presumptive peptide was a blur. And the reason for that was instantly obvious, even to me: It was not a single peptide, it was a composite of hundreds or thousands of different peptides, all superimposed on each other. That blur was the secret of MHC specificity, and of MHC complexity. Again, a very physically satisfying explanation.

Wiley’s group had a second article, back to back with this first, on the “Foreign antigen binding site and T cell recognition regions” of the protein. Here they raked together a vast, scattered literature — functional residues, polymorphisms, antibody binding sites, transplant rejections — and showed that it all made sense. Everything could be set into place on the structure they’d shown. Among other things, they predicted that the T cell receptor would bind on top of the “foreign antigen binding site” (remember that going in, there was no direct evidence that antigens even bound to the MHC class I, let alone to any particular site; nor was the T cell receptor identified), recognizing both MHC and peptide residues. They identified contact residues for peptide and for TcR, explained how polymorphisms contributed to diversity … They took the jigsaw puzzle from an outline and a few pieces of blue sky and grass, all the way through the final picture (kindly leaving a few small pieces unplaced, for the rest of us to fill in.)

This second paper was less physical, more cerebral, and it took me longer to understand most of their arguments. It didn’t matter. They had me from that little blue-on-black square in the first paper, and I was happy to spend the time reading and thinking that the second paper needed.

Bjorkman, P. J., Saper, M. A., and Wiley, D. C. (1987). Structure of human class I histocompatibility antigen, HLA-A2. Nature 329, 506-512.

Bjorkman, P. J., Saper, M. A., Samraoui, B., Benett, W. S., Strominger, J. L., and Wiley, D. C. (1987). The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329, 512-518.

  1. My first son was born on Oct 8, exactly 12 years later, but I swear it was a coincidence. (He is getting a new bike for his birthday, if anyone is interested.) []
  2. All quotes are from the papers in question, from Pamela Bjorkman, in Don Wiley’s lab. []
  3. Remember that this this is all my own viewpoint, and at the time I was a very new student — it’s quite possible that some, or even many, people in the field were more aware of the possibilities than I was. But I think it’s a generally fair statement.[]
  4. I may have got this wrong, but I believe that, in those almost-pre-computer days, Figure 2a was drawn, by hand, by Hidde Ploegh, then a post-doc in the Strominger lab.[]
  5. Relatively speaking — at 3.6 Ã… it is by today’s standards a low-resolution structure[]