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G Protein Coupled Receptors (GPCRs) are a large family of seven transmembrane (TM) helical structural motif containing proteins that regulate cellular communication. Based on sequence similarity within the seven TM segment in human, the major five GPCR families are rhodopsin,secretin, glutamate, adhesion and frizzled/taste. GPCRs are principle signal transducer that activate senses of sight, smell and test, and responsible for many signaling disorders and diseases. Molecular mechanisms of GPCR activation are always implicated as a therapeutic purpose to discover new drug targets. Several molecular mechanisms and models of GPCR activation have been proposed. Dimerization, protonation, conformations due to intramolecular interaction and specific conformational changes are thought to be responsible for receptor activation. In this review, these mechanisms and proposed model systems are discussed in detail.