Chromogranin A (CgA), which is an intrinsically disordered protein that belongs to the granin family, was first discovered in the bovine adrenal medulla, and later identified in various organs. Under certain physiological conditions, CgA is cleaved into functionally diverse peptides, such as vasostatin-1, pancreastatin, and catestatin. In this review, we first describe the historical and systematic challenges for elucidating the molecular structures of CgA and its derived peptides and give a perspective of utilizing emerging techniques through integrative approaches. Subsequently, we review specific biological processes associated with CgA and its derived peptides in the neuroendocrine, immune, and digestive systems. Finally, we discuss biomedical applications of CgA as a biomarker, suggesting future directions toward translational and precision medicine.

ranging from 0.4 to 23 mM. The other class of molecules are halogenated cisimidazoline analogs such as Nutlin-3a that inhibit MDM2 with IC50 values ranging from 0.086 to 26 mM. To study the thermodynamics and kinetics of binding for these inhibitors, we build multi-ensemble Markov models (MEMMs) from explicit-solvent molecular dynamics trajectories of the binding/unbinding reactions biased by umbrella sampling (US) and scaled nonbonded interactions. This methodology allows us to observe significantly more binding and unbinding events than would be observed with unbiased sampling. We discuss the accuracy of estimated affinities and binding kinetics.

Across the domains of life, the molecular clock allows organisms to anticipate and respond to time-dependent events. At the center of the clock resides the core circadian oscillator, a tunable molecular timekeeper that maintains rhythms while also activating output pathways. While much has been learned regarding the molecular machinations of clocks, there remains a dearth of structural knowledge describing the details of oscillator function. In the cyanobacterial system, a phosphorylationrdephsophorylation cycle in the AAAþ ATPase KaiC governs rhythms within the S. elongatus cell. While it has been demonstrated that different phosphoforms of KaiC are biochemically distinct, having differing affinities for the other Kai proteins and ATPase rates, crystallization studies have been unable to detect significant structural changes in KaiC as it progresses throughout its circadian cycle. Our work on the cyanobacterial oscillator resolves this discrepancy by utilizing the technique of cryo-electron microscopy (Cryo-EM), a powerful tool for structural characterization that does not require sample crystallization. We have observed new conformations of KaiC in phophomimetic mutants that recapitulate KaiC at different circadian timepoints. Our results show that KaiC undergoes large structural changes that are dependent upon its phosphorylation state.