AbstractChemokines are small secreted proteins that play an important role in immune responses and have also been shown to be involved in cartilage development and contributing to pathogenesis of a variety of diseases. They present a conserved 3D structure, so‐called IL8‐like chemokine fold, which is supported by conserved cysteines forming intra‐molecular disulfide bonds. These cysteine sequence motifs have often been used to find new chemokine family members by sequence‐based database searches. However, it has been shown that different patterns can provide disulfide bonds fitting into an IL8‐like architecture, which has been the key to identify new remote homologues of the IL8‐like chemokine family. We report a structural–functional characterization of cytokine‐like protein 1 (Cytl1) by a combination of different computational structure‐based techniques. Previous studies based on sequence analysis and secondary structure predictions reported that Cytl1 might adopt a 4‐helical cytokine fold. However, our detailed molecular modeling studies and structure‐based functional analysis strongly suggest that Cytl1 is more likely to adopt an IL8‐like chemokine fold, in particular similar to CCL2 (monocyte chemoattractant protein 1, MCP‐1). Moreover, we identify in a CCL2‐like 3D model of Cytl1 the necessary reported features to signal through the chemokine receptor CCR2. Those discovered structural features of Cytl1 as CCL2‐like chemokine, together with the fact that both, CCL2 and Cytl1, are known to be involved in cartilage development and pathogenesis of osteoarthritis and rheumatoid arthritis, make us hypothesize that Cytl1 could be a structurally and functionally related analog of CCL2 signaling through the chemokine receptor CCR2. Proteins 2011. © 2011 Wiley‐Liss, Inc.