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Human adenovirus type 36 (HAdV-D36) has been putatively linked to obesity in animals and has been associated with obesity in humans in some but not all studies. Despite extensive epidemiological research there is limited information about its receptor profile. We investigated the receptor portfolio of HAdV-D36 using a combined structural biology and virology approach. The HAdV-D36 fiber knob domain (FK), which mediates the primary attachment of many HAdVs to host cells, has a significantly elongated DG loop that alters known binding interfaces for established adenovirus receptors such as the coxsackie- and adenovirus receptor (CAR) and CD46. Our data suggest that HAdV-D36 attaches to host cells using a versatile receptor pool comprising sialic acid-containing glycans and CAR. Sialic acids are recognized at the same binding site used by other HAdVs of species D such as HAdV-D37. Using glycan microarrays, we demonstrate that HAdV-D36 displays a binding preference for glycans containing a rare sialic acid variant, 4-O,5-N-diacetylneuraminic acid, over the more common 5-N-acetylneuraminic acid. To date, this sialic acid variant has not been detected in humans, although it can be synthesized by various animal species, including a range of domestic and livestock animals. Taken together, our results indicate that HAdV-D36 has evolved to recognize a specialized set of primary attachment receptors that are different from known HAdV types and coincides with a unique host range and pathogenicity profile. Author summary: Most human adenoviruses do not infect animals. HAdV-D36 stands out, as it can infect a wide range of animals and cause obesity in them. It is also associated with obesity in humans. Here, we demonstrate that HAdV-D36 can use a diacetylated sialic acid monosaccharide (4-O-acetyl-Neu5Ac) as a cellular receptor. 4-O-acetyl-Neu5Ac is synthesized in animal cells but not in human cells. In humans, 4-O-acetyl-Neu5Ac is expected to be metabolized upon dietary intake and presented on cells in similarity with other non-human sialic acids. We conclude that HAdV-D36 has evolved to recognize a distinct receptor that is different from those used by other human adenoviruses. [ABSTRACT FROM AUTHOR]