Abstract
Cyclic guanosine 3′,5′‐monophosphate (cGMP) is an intracellular signalling molecule involved in many sensory and developmental processes. Synthesis of cGMP from GTP is catalysed by guanylate cyclase (GC) in a reaction analogous to cAMP formation by adenylate cyclase (AC). Although detailed structural information is available on the catalytic region of nucleotidyl cyclases (NCs) in various states, these atomic models do not provide a sufficient explanation for the substrate selectivity between GC and AC family members. Detailed structural information on the GC domain in its active conformation is largely missing, and no crystal structure of a GTP‐bound wild‐type GC domain has been published to date. Here, we describe the crystal structure of the catalytic domain of rhodopsin–GC (RhGC) from Catenaria anguillulae in complex with GTP at 1.7 Å resolution. Our study reveals the organization of a eukaryotic GC domain in its active conformation. We observe that the binding mode of the substrate GTP is similar to that of AC–ATP interaction, although surprisingly not all of the interactions predicted to be responsible for base recognition are present. The structure provides insights into potential mechanisms of substrate discrimination and activity regulation that may be common to all class III purine NCs.DatabaseStructural data are available in Protein Data Bank database under the accession number 6SIR.Enzymes EC4.6.1.2.
Highlights
Guanylate cyclases (GCs) convert guanosine 50triphosphate (GTP) into one of the most important intracellular messengers, cyclic guanosine 30,50monophosphate. cGMP is central to many transduction pathways where it propagates signals in processes that include neurotransmission, blood pressure regulation, bone growth, lipolysis or muscle contraction [1]
RhGC is anticipated to act as a dimer like all other GCs [29,30], the isolated GC domain is monomeric in solution (Fig. 1B and [20])
These crystals diffracted to 1.7 A resolution, and we solved the structure of CaGCÁGTPÁCa2+ by molecular replacement as described further below
Summary
Guanylate cyclases (GCs) convert guanosine 50triphosphate (GTP) into one of the most important intracellular messengers, cyclic guanosine 30,50monophosphate (cGMP). cGMP is central to many transduction pathways where it propagates signals in processes that include neurotransmission, blood pressure regulation, bone growth, lipolysis or muscle contraction [1]. Guanylate cyclases (GCs) convert guanosine 50triphosphate (GTP) into one of the most important intracellular messengers, cyclic guanosine 30,50monophosphate (cGMP). All GCs belong to the class III nucleotidyl cyclase (NC) family that includes many adenylate cyclases (ACs), which perform an analogous function of converting adenosine 50-triphosphate (ATP) to cyclic adenosine 30,50-monophosphate. Class III ACs and GCs are widely distributed through all kingdoms of life and are closely related in primary sequence [2]. They have evolved as dimeric head-to-tail wreath-like assemblies with the active site (s) formed at the interface between the catalytic subunits/subdomains [3]
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