Tables for
Volume F
Crystallography of biological macromolecules
Edited by E. Arnold, D. M. Himmel and M. G. Rossmann

International Tables for Crystallography (2012). Vol. F, ch. 1.3, p. 26   | 1 | 2 |

Section 1.3.5. Vaccines, immunology and crystallography

W. G. J. Hola* and C. L. M. J. Verlindea

aBiomolecular Structure Center, Department of Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195–7742, USA
Correspondence e-mail:

1.3.5. Vaccines, immunology and crystallography

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Vaccines are probably the most effective way of preventing disease. An impressive number of vaccines have been developed and many more are under development (National Institute of Allergy and Infectious Diseases, 1998[link]). Smallpox has been eradicated thanks to a vaccine, and polio is being targeted for eradication in a worldwide effort, again using vaccination strategies. To the best of our knowledge, crystal structures of viruses, viral capsids or viral proteins have not been used in developing the currently available vaccines. However, there are projects underway that may change this.

For instance, the crystal structure of rhinovirus has resulted in the development of compounds that have potential as antiviral agents, since they stabilize the viral capsid and block, or at least delay, the uncoating step in viral cell entry (Fox et al., 1986[link]). These rhinovirus capsid-stabilizing compounds are, in a different project, being used to stabilize poliovirus particles against heat-induced denaturation in vaccines (Grant et al., 1994[link]). This approach may be applicable to other cases, although it has not yet resulted in commercially available vaccine-plus-stabilizer cocktails. However, it is fascinating to see how a drug-design project may be able to assist vaccine development in a rather unexpected manner.

Three-dimensional structural information about viruses is also being used to aid in the development of vaccines. Knowledge of the architecture of and biological functions of coat proteins has been used to select loops at viral surfaces that can be replaced with antigenic loops from other pathogens for vaccine-engineering purposes (e.g. Burke et al., 1988[link]; Kohara et al., 1988[link]; Martin et al., 1988[link]; Murray et al., 1998[link]; Arnold et al., 1994[link]; Resnick et al., 1995[link]; Smith et al., 1998[link]; Arnold & Arnold, 1999[link]; Zhang, Geisler et al., 1999[link]). The design of human rhinovirus (HRV) and poliovirus chimeras has been aided by knowing the atomic structure of the viruses (Hogle et al., 1985[link]; Rossmann et al., 1985[link]; Arnold & Rossmann, 1988[link]; Arnold & Rossmann, 1990[link]) and detailed features of the neutralizing immunogenic sites on the virion surfaces (Sherry & Rueckert, 1985[link]; Sherry et al., 1986[link]). In this way, one can imagine that in cases where the atomic structures of antigenic loops in `donor' immunogens are known as well as the structure of the `recipient' loop in the virus capsid protein, optimal loop transplantation might become possible. It is not yet known how to engineer precisely the desired three-dimensional structures and properties into macromolecules. However, libraries of macromolecules or viruses constructed using combinatorial mutagenesis can be searched to increase the likelihood of including structures with desired architecture and properties such as immunogenicity. With appropriate selection methods, the rare constructs with desired properties can be identified and `fished out'. Research of this type has yielded some potently immunogenic presentations of sequences transplanted on the surface of HRV (reviewed in Arnold & Arnold, 1999[link]). For reasons not quite fully understood, presenting multiple copies of antigens to the immune system leads to an enhanced immune response (Malik & Perham, 1997[link]). It is conceivable that, eventually, it might even be possible for conformational epitopes consisting of multiple `donor' loops to be grafted onto `recipient capsids' while maintaining the integrity of the original structure. Certainly, such feats are difficult to achieve with present-day protein-engineering skills, but recent successes in protein design offer hope that this will be feasible in the not too distant future (Gordon et al., 1999[link]).

Immense efforts have been made by numerous crystallographers to unravel the structures of molecules involved in the unbelievably complex, powerful and fascinating immune system. Many of the human proteins studied are listed in Table[link] with, as specific highlights, the structures of immunoglobulins (Poljak et al., 1973[link]), major histocompatibility complex (MHC) molecules (Bjorkman et al., 1987[link]; Brown et al., 1993[link]; Fremont et al., 1992[link]; Bjorkman & Burmeister, 1994[link]), T-cell receptors (TCR) and MHC:TCR complexes (Garboczi et al., 1996[link]; Garcia et al., 1996[link]), an array of cytokines and chemokines, and immune cell-specific kinases such as lck (Zhu et al., 1999[link]). This knowledge is being converted into practical applications, for instance by humanising non-human antibodies with desirable properties (Reichmann et al., 1988[link]) and by creating immunotoxins.

The interactions between chemokines and receptors, and the complicated signalling pathways within each immune cell, make it next to impossible to predict the effect of small compounds interfering with a specific protein–protein interaction in the immune system (Deller & Jones, 2000[link]). However, great encouragement has been obtained from the discovery of the remarkable manner by which the immunosuppressor FK506 functions: this small molecule brings two proteins, FKB12 and calcineurin, together, thereby preventing T-cell activation by calcineurin. The structure of this remarkable ternary complex is known (Kissinger et al., 1995[link]). Such discoveries of unusual modes of action of therapeutic compounds are the foundation for new concepts such as `chemical dimerizers' to activate signalling events in cells such as apoptosis (Clackson et al., 1998[link]).

In spite of the gargantuan task ahead aimed at unravelling the cell-to-cell communication in immune action, it is unavoidable that the next decades will bring us unprecedented insight into the many carefully controlled processes of the immune system. In turn, it is expected that this will lead to new therapeutics for manipulating a truly wonderful defence system in order to assist vaccines, to decrease graft rejection processes in organ transplants and to control auto-immune diseases that are likely to be playing a major role in cruelly debilitating diseases such as rheumatoid arthritis and type I diabetes.


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