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A study provides evidence to support the notion that four residues in IbTX accounts for all of its specificity for calcium-activated potassium (BK) versus voltage-gated potassium (KV) channels. It is found that current structural models of [alpha]-KTx complexes do not accurately predict these IbTX specificity determinants.

Specific, rapid association of protein complexes is essential for all forms of cellular existence. The initial association of two molecules in diffusion-controlled reactions is often influenced by the electrostatic potential. Yet, the detailed binding mechanisms of proteins highly depend on the particular system. A complete protein complex formation pathway has been delineated by using structural information sampled over the course of the transformation reaction. The pathway begins at an encounter complex that is formed by one of the apo forms of neurotoxin fasciculin-2 (FAS2) and its high-affinity binding protein, acetylcholinesterase (ACHE), followed by rapid conformational rearrangements into an intermediate complex that subsequently converts to the final complex as observed in crystal structures. Formation of the intermediate complex has also been independently captured in a separate 20-ns molecular dynamics simulation of the encounter complex. Conformational transitions between the apo and liganded states of FAS2 in the presence and absence of AChE are described in terms of their relative free energy profiles that link these two states. The transitions of FAS2 after binding to AChE are significantly faster than in the absence of ACHE; the energy barrier between the two conformational states is reduced by half. Conformational rearrangements of FAS2 to the final liganded form not only bring the FAS2/AChE complex to lower energy states, but by controlling transient motions that lead to opening or closing one of the alternative passages to the active site of the enzyme also maximize the ligand's inhibition of the enzyme. conformational transitions | protein-protein binding

A novel contoxin inhibitor of Kv 1.6 channel and nicotinic acetylcholine receptor (nACHR) subtypes are used to define a new family of conotoxins, named p114a that has a potent activity at the nACHR subtypes, as well as the voltage-gated potassium channel subtype. The results show that there exist many similarities between the middle loop of p114a and the second loop of many other conotoxins though it is the first conotoxin to affect both the activities simultaneously.

Crystal structures of eosinophil-derived neurotoxin (EDN) are reported in complex with 5-ATP, Ap3A, Ap4A and Ap5A. The structures reveal how the extensions of the ppA core outward from the beta phosphate affects the mode of binding and suggest how improved inhibitors can be generated.

Photosystem I (PSI) meditates light-driven transmembrane electron transfer, in photosynthetic membranes of cyanobacteria, algae and higher plants. The excitation energy for the functioning of the primary electron donor in the RC is delivered with peripheral light-harvesting antennas.

The characterization of the copper(II) complex species formed with the PrP106-126 peptide bearing both C- and N-termini protected by acetylation and amidation, respectively (HuPrPAc106-126NH2) is reported. The results concerning the copper(II) complexes with Hu-PrPAc106-126NH2 and the related fragments allow a reliable comparison between the metal ions affinities of the two binding sites located within the disordered region, showing the coordination features of the main species formed in the physiological pH range.

A novel, physiologically relevant method (oligomer cross-seeding) was used to generate and characterize homogeneous populations of tau oligomers. The results revealed that both A[beta] and [alpha]-synuclein oligomers induce tau aggregation and the formation of [beta]-sheet-rich neurotoxic tau oligomers.

An efficient chemical synthesis of the ABCDEFG segment of maitotoxin was developed to provide further support for maitotoxin structure and facilitate fragment-based biological studies. The close match revealed through the [super 13]C NMR chemical shift comparisons of the synthetic ABCDEFG segment of maitotoxin with the corresponding values for the same carbons of maitotoxin provide evidence for the accuracy of the originally assigned structure to this polycyclic system of the natural product.

The X-ray crystal structure of a complex between the Clostridium botulinum neurotoxin serotype A light chain (BoNT/A-LC) and the inhibitory peptide N-Ac-CRATKML, the first structure of the light chain with an inhibitory peptide bound at the catalytic Zn(II) ions are reported. The two structures are found to be nearly similar and confirm the significant catalytic role played by Zn(II) ion.

The structural studies about a natural mutant of [alpha]-insect toxins, Buthus martensii Karsch, BmK[alpha]IT01, which shows high toxicity to insect and moderate toxicity to mammal is presented. Results indicate that BmK[alpha]IT01 shares a structure similar to scorpion [alpha]-toxins.

The structural elucidation and total synthesis of azaspiracid-1, a neurotoxin isolated from mussels, are reported. Along with the total synthesis of azaspiracid-1, the syntheses of its C1-C20 epimer and of several truncated analogues for biological investigations are described.

The 2.3 Angstrom crystal structure of tetanus neurotoxin light chain (TeNT-LC), determined by combined molecular replacement and MAD phasing is reported. The results reveal TeNT is the causative agent of the neuroparalytic disease tetanus.

The structure and stability of a human Ser112Ile transthyretin variant is investigated and demonstrated that the Ser112Ile variant exists as a dimer having nonnative tertiary structure at physiological pH. The results describe the importance of an unstable dimeric structure in forming spherical aggregates that induces cell death in a human neuroblastoma cell line.

The stereoselective total synthesis of brevetoxin-B (BTX-B) via the coupling of phosphonium salt and IJK-ring system is reported. The results show that the total synthesis of BTX-B was efficiently achieved with high stereoselectivity in 59 steps as the longest sequence (tri-O-acetyl-D-glucal forward arrow BTX-B (1)) and in total 90 steps with an average of 93% yield for each step.

Chromogenic properties of various candidate structures has been calculated using density functional theory. Results indicate that isoindole monomers should not exhibit color, whereas isoindole derivative dimers should be colored.

A new approach to the total synthesis of gambierol, a potent neurotoxin isolated from the cultured cells of Gambierdiscus toxicus, is proposed. The convergent total synthesis of gambierol is achieved by using intramolecular alkylation of alpha-chloroacetoxy ether and subsequent ring-closing metathesis.