ATP binding cassette (ABC) exporters contain a pair of nucleotide-binding domains (NBDs), which bind and hydrolyze ATP to pump substrates across the membrane. Functional studies suggest that the two ATP binding sites are conformationally coupled. In contrast to other ABC exporters, we show that the asymmetric NBDs of the heterodimeric ABC exporter TM287/288 remain in contact, even in the absence of nucleotides. By comparing the apo state with the adenosine 5′-(β,γ-imido)triphosphate–bound structure of TM287/288, we unravel the structural basis for allosteric coupling between the ATP binding sites. NBD-NBD contacts in the inward-facing transporter warrant cross-communication between the ATP binding sites throughout the transport cycle and are in agreement with functional models of clinically important heterodimeric ABC exporters including CFTR, SUR1, and TAP1/2.