The heme-based sensor proteins become a new family of hemeproteins that show a new biological function as the sensor for gas molecules such as O2, CO, and NO.These gas molecules can act as signaling molecules for the regulation of biological signal transduction systems. These regulatory systems consist of a sensor and regulatory domains/proteins, in which the sensor domain/protein senses the physiological gas molecule and then regulates the biological function of the regulatory domain/protein via intra- or inter-molecular signal transduction between the sensor and regulatory domains/proteins. The heme-based sensor domain/protein senses a gas molecule as its physiological effector by binding it to the heme in the sensor domain/protein. Though the heme-based sensor proteins adopt several different domains including H-NOX, globin, PAS, and GAF domains as the sensor domain in which the heme is accommodated, it is common among the heme-based sensors/proteins that gas-binding to the heme triggers the signal transduction process to regulate the regulatory domain/protein, which is initiated by a conformational change around the heme upon gas-binding. The interactions between the heme-bound ligand and surrounding amino acid residues will play an important role for distinguishing the physiological gas molecule among other heme-binding ligands and for the conformational change responsible for signal transduction. Thus, structural information of the sensor domain/protein is essential to elucidate the molecular mechanisms of gas-sensing and functional regulation by the heme-based sensor proteins. In this work, we have elucidated the structure-function relationships of several heme-based sensor proteins including HemAT, Aer2, HemDGC. While HemAT and Aer2 are signal transducer proteins in the aerotaxis regulatory systems, HemDGC is a heme-containing diguanylate cyclase that consists of the N-terminal sensor domain and the C-terminal diguanylate cyclase domain. We have determined the X-ray crystal structures of Aer2-N384 (residues 1-384 that consists of three-HAMP, PAS, and di-HAMP) and Aer2-PH (residues 173-384 that consists of PAS and di-HAMP) to elucidate the mechanism by which intramolecular signal transduction proceeds between the HAMP and PAS domains in Aer2. Aer2-N384 is a homodimer having a non-crystallographic 2-fold symmetry. The three-unit poly-HAMP, PAS, and di-HAMP domains are ordered in linear configuration. A heme exists in a hydrophobic pocket in the PAS domain. His234 serves as the proximal ligand of the heme. The structural analyses of Aer2 suggests that the heme-bound O2 forms a hydrogen bond with Trp283. Trp283 is located on the C-terminal of the strand b5. This strand connects to the helix a5, which is the starting region of the C-terminal di-HAMP domain, suggesting that the hydrogen bond between Trp283 and O2 are responsible for intramolecular signal transduction. The enzymatic activity of HemDGC is regulated by the ligand binding to the heme. The enzymatic activity for the formation of c-di-GMP from GTP was measured for ferric, cyanomet, deoxy, oxy, CO-bound, and NO-bound HemDGC. Only oxy HemDGC showed the activity of diguanylate cyclase for the formation of c-di-GMP from GTP, but ferric, cyanomet, deoxy, CO-bound, and NO-bound HemDGC did not at all. These results indicate that O2 will be a physiological effector of HemDGC and will regulate the enzymatic activity of HemDGC via the formation of the oxy-complex of the heme. Thus, the globin domain of HemDGC acts as a sensor that can strictly discriminate O2 among external ligands capable to bind to the heme. HemDGC shows different hydrogen bonding patterns between the O2- and CO-bound forms. Resonance Raman spectroscopy reveals that Tyr55 forms a hydrogen bond with the heme-bound O2, but not with CO. Instead, Gln81 interacts with the heme-bound CO. These differences of a hydrogen bonding network will play a crucial role for the selective O2 sensing responsible for the regulation of the enzymatic activity.