To reconcile the difference with the recently reported rat PAH full-length structure, which did not reveal ACT:ACT interactions in the unliganded form12, we propose that the rat full-length PAH structure in the absence of Phe and our human PAH-RD structure in the presence of Phe could represent the unliganded ‘active-site blocking mode’ and the Phe-bound ‘multimerization mode’ of the domain, respectively. This evidence concerns the gene PAH and pulmonary arterial hypertension.