TY - JOUR
T1 - Sequence, structure, function, immunity
T2 - Structural genomics of costimulation
AU - Chattopadhyay, Kausik
AU - Lazar-Molnar, Eszter
AU - Yan, Qingrong
AU - Rubinstein, Rotem
AU - Zhan, Chenyang
AU - Vigdorovich, Vladimir
AU - Ramagopal, Udupi A.
AU - Bonanno, Jeffrey
AU - Nathenson, Stanley G.
AU - Almo, Steven C.
PY - 2009/5
Y1 - 2009/5
N2 - Costimulatory receptors and ligands trigger the signaling pathways that are responsible for modulating the strength, course, and duration of an immune response. High-resolution structures have provided invaluable mechanistic insights by defining the chemical and physical features underlying costimulatory receptor:ligand specificity, affinity, oligomeric state, and valency. Furthermore, these structures revealed general architectural features that are important for the integration of these interactions and their associated signaling pathways into overall cellular physiology. Recent technological advances in structural biology promise unprecedented opportunities for furthering our understanding of the structural features and mechanisms that govern costimulation. In this review, we highlight unique insights that have been revealed by structures of costimulatory molecules from the immunoglobulin and tumor necrosis factor superfamilies and describe a vision for future structural and mechanistic analysis of costimulation. This vision includes simple strategies for the selection of candidate molecules for structure determination and highlights the critical role of structure in the design of mutant costimulatory molecules for the generation of in vivo structure-function correlations in a mammalian model system. This integrated 'atoms-to-animals' paradigm provides a comprehensive approach for defining atomic and molecular mechanisms.
AB - Costimulatory receptors and ligands trigger the signaling pathways that are responsible for modulating the strength, course, and duration of an immune response. High-resolution structures have provided invaluable mechanistic insights by defining the chemical and physical features underlying costimulatory receptor:ligand specificity, affinity, oligomeric state, and valency. Furthermore, these structures revealed general architectural features that are important for the integration of these interactions and their associated signaling pathways into overall cellular physiology. Recent technological advances in structural biology promise unprecedented opportunities for furthering our understanding of the structural features and mechanisms that govern costimulation. In this review, we highlight unique insights that have been revealed by structures of costimulatory molecules from the immunoglobulin and tumor necrosis factor superfamilies and describe a vision for future structural and mechanistic analysis of costimulation. This vision includes simple strategies for the selection of candidate molecules for structure determination and highlights the critical role of structure in the design of mutant costimulatory molecules for the generation of in vivo structure-function correlations in a mammalian model system. This integrated 'atoms-to-animals' paradigm provides a comprehensive approach for defining atomic and molecular mechanisms.
KW - Immunoglobulin superfamily
KW - Structure
KW - T-cell costimulation
KW - TNF/TNFR superfamily
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U2 - 10.1111/j.1600-065X.2009.00778.x
DO - 10.1111/j.1600-065X.2009.00778.x
M3 - Review article
C2 - 19426233
AN - SCOPUS:65349102966
SN - 0105-2896
VL - 229
SP - 356
EP - 386
JO - Immunological Reviews
JF - Immunological Reviews
IS - 1
ER -