NMR spectroscopy and X-ray crystallography are currently the two most widely applied methods for the determination of macromolecular structure at high resolution. More recently, significant advances have been made in algorithms for de novo prediction of protein structure, and in favorable cases, the predicted models agree extremely well with experimentally determined structures. This study from the Williamson lab demonstrates a synergistic combination of NMR spectroscopy, de novo structure prediction, and X-ray crystallography in an effective overall strategy for rapidly determining the structure of the coat protein C-terminal domain from the Sulfolobus islandicus rod-shaped virus (SIRV). The most accessible information from each structural technique is taken advantage of in this approach, and it may be widely applicable for structure determination.