Biological and artificial molecules and assemblies capable of supramolecular recognition, especially those with nucleobase pairing,u sually rely on autonomous or collective binding to function. Advanced site-specific recognition takes advantage of cooperative spatial effects,a si nl ocal folding in protein-DNAb inding.H erein, we report an ew nucleobasetagged metal-organic framework (MOF), namely ZnBTCA (BTC = benzene-1,3,5-tricarboxyl, A = adenine), in whicht he exposed Watson-Crickf aces of adenine residues are immobilized periodically on the interior crystalline surface.Systematic control experiments demonstrated the cooperation of the open Watson-Crick sites and spatial effects within the nanopores, and thermodynamic and kinetic studies revealed ah ysteretic host-guest interaction attributed to mild chemisorption. We further exploited this behavior for adenine-thymine binding within the constrained pores,and aglobally adaptive response of the MOF host was observed.