Significance Reengineering naturally occurring proteins to have new functions has had considerable impact on industrial and biomedical applications, but is limited by the finite number of known proteins. A promise of de novo protein design is to generate a larger and more diverse set of protein structures than is currently available. This vision has not yet been realized for small-molecule binder or enzyme design due to the complexity of pocket-containing structures. Here we present an algorithm that systematically generates NTF2-like protein structures with diverse pocket geometries. The scaffold sets, the insights gained from detailed structural characterization, and the computational method for generating unlimited numbers of structures should contribute to a new generation of de novo small-molecule binding proteins and catalysts.