A consensus-binding structure for adenine at the atomic level permits searching for the ligand site in a wide spectrum of adenine-containing complexes

Attempts to derive structural features of ligand‐binding sites have traditionally involved seeking commonalities at the residue level. Recently, structural studies have turned to atomic interactions of small molecular fragments to extract common binding‐site properties. Here, we explore the use of larger ligand elements to derive a consensus binding structure for the ligand as a whole. We superimposed multiple molecular structures from a nonredundant set of adenosine‐5′‐triphosphate (ATP) protein complexes, using the adenine moiety as template. Clustered binding‐site atoms of compatible atomic classes forming attractive contacts with the adenine probe were extracted. A set of atomic clusters characterizing the adenine binding pocket was then derived. Among the clusters are three vertices representing the interactions of adenine atom N6 with its protein‐binding niche. These vertices, together with atom C6 of the purine ring system, complete the set of four vertices for the pyramid‐like structure of the N6 anchor atom. Also, the sequence relationship for the adenine‐binding loop interacting with the C2–N6 end of the conjugated ring system is expanded to include a third hydrophilic cluster interacting with atom N1. A search procedure involving interatomic distances between cluster centers was formulated and applied to seek putative binding sites in test cases. The results show that a consensus network of clusters, based on an adenine probe and an ATP‐complexed training set of proteins, is sufficient to recognize the experimental cavity for adenine in a wide spectrum of ligand–protein complexes. Proteins 2003;52:400–411. © 2003 Wiley‐Liss, Inc.