The present invention comprises crystalline polyketide synthases, isolated non-native polyketide synthases having the structural coordinates of said crystalline polyketide synthases, and nucleic acids encoding such non-native polyketide synthases. Also disclosed are methods of predicting the activity and/or substrate specificity of putative polyketide synthase, methods of identifying potential polyketide synthase substrates, and methods of identifying potential polyketide synthase inhibitors.