The 1918 influenza pandemic resulted in about 20 million deaths. This enormous impact, coupled with renewed interest in emerging infections, makes characterization of the virus involved a priority. ...Receptor binding, the initial event in virus infection, is a major determinant of virus transmissibility that, for influenza viruses, is mediated by the hemagglutinin (HA) membrane glycoprotein. We have determined the crystal structures of the HA from the 1918 virus and two closely related HAs in complex with receptor analogs. They explain how the 1918 HA, while retaining receptor binding site amino acids characteristic of an avian precursor HA, is able to bind human receptors and how, as a consequence, the virus was able to spread in the human population.
Abstract Oseltamivir, one of the two anti-neuraminidase drugs, is currently the most widely used drug against influenza. Resistance to the drug has occurred infrequently among different viruses in ...response to drug treatment, including A H5N1 viruses, but most notably has emerged among recently circulating A H1N1 viruses and has spread throughout the population in the absence of drug use. Crystal structures of enzyme–drug complexes, together with enzymatic properties, of mutants of H5N1 neuraminidase have provided explanations for high level oseltamivir resistance due to the common H275Y mutation, with retention of zanamivir susceptibility, and intermediate level resistance due to the N295S mutation. Complementation of enhanced NA activity due to a D344N mutation by the H275Y mutation suggests an explanation for the recent emergence and predominance of oseltamivir-resistant influenza A H1N1 viruses.
Small G proteins are GTP-dependent molecular switches that regulate numerous cellular functions. They can be classified into homologous subfamilies that are broadly associated with specific ...biological processes. Cross-talk between small G-protein families has an important role in signalling, but the mechanism by which it occurs is poorly understood. The coordinated action of Arf and Rho family GTPases is required to regulate many cellular processes including lipid signalling, cell motility and Golgi function. Arfaptin is a ubiquitously expressed protein implicated in mediating cross-talk between Rac (a member of the Rho family) and Arf small GTPases. Here we show that Arfaptin binds specifically to GTP-bound Arf1 and Arf6, but binds to Rac·GTP and Rac·GDP with similar affinities. The X-ray structure of Arfaptin reveals an elongated, crescent-shaped dimer of three-helix coiled-coils. Structures of Arfaptin with Rac bound to either GDP or the slowly hydrolysable analogue GMPPNP show that the switch regions adopt similar conformations in both complexes. Our data highlight fundamental differences between the molecular mechanisms of Rho and Ras family signalling, and suggest a model of Arfaptin-mediated synergy between the Arf and Rho family signalling pathways.
An understanding of the structural determinants and molecular mechanisms involved in influenza A virus binding to human cell receptors is central to the identification of viruses that pose a pandemic ...threat. To date, only a limited number of viruses are known to have infected humans even sporadically, and this has recently included the virulent H5 and H7 avian viruses. We compare here the 3-dimensional structures of H5 and H7 hemagglutinins (HA) complexed with avian and human receptor analogues, to highlight regions within the receptor binding domains of these HAs that might prevent strong binding to the human receptor.
Immune checkpoint inhibitor–induced hypophysitis is a rare complication of pembrolizumab, but the effects of drug‐induced hypophysitis on preexisting pituitary lesions are unknown. The authors ...treated an unusual case of pembrolizumab‐induced hypophysitis that resulted in acute exacerbation of a preexisting pituitary cystic lesion causing severe intractable headaches. Before initiation of pembrolizumab therapy, magnetic resonance imaging should be carefully reviewed for sellar pathology. Patients demonstrating a Rathke's cleft cyst should consider other forms of treatment first or be carefully counseled before pembrolizumab initiation, because the advent of hypophysitis could result in symptomatic progression of an existing lesion, necessitating urgent surgical intervention.
Immune checkpoint inhibitor–induced hypophysitis is a rare complication of pembrolizumab, but the effects of drug‐induced hypophysitis on preexisting pituitary lesions are unknown. The authors successfully treated an unusual case of pembrolizumab‐induced hypophysitis that resulted in acute exacerbation of a preexisting pituitary cystic lesion causing severe intractable headaches via a microscopic transnasal transsphenoidal resection. Before treatment with pembrolizumab, patients should undergo MRI of the brain to review for sellar pathology and should be offered other forms of treatment if such is found, because the advent of hypophysitis could result in symptomatic progression, necessitating urgent surgical intervention.
Comparing the structures of H3, H5 and H9 subtype haemagglutinins, we deduced a structural basis for including all 15 influenza subtypes in four clades. H3, H5 and H9 represent three of these clades; ...we now report the structure of an H7 HA as a representative of the fourth clade. We confirm the structure of the turn at the N-terminus of the conserved central α-helix of HA2, and the combination of ionisable residues near the “fusion peptide” as clade-specific features. We compare the structures of three H1 HAs with H5 HA in the same clade, to refine our previous classification and we confirm the division of the clades into two groups of two. We also show the roles of carbohydrate side chains in the esterase-fusion domain boundaries in the formation of clade-specific structural markers.
•We report the structures of 4 sialoside receptor analogues complexed with H5 HA.•The analogues included fucosylated and/or sulphated GlcNAc at position 3.•Estimates of affinity of HA for the ...analogues were made by biolayer interferometry.
The crystal structure of a large fragment of yeast type II DNA topoisomerase reveals a heart-shaped dimeric protein with a large central hole. It provides a molecular model of the enzyme as an ...ATP-modulated clamp with two sets of jaws at opposite ends, connected by multiple joints. An enzyme with bound DNA can admit a second DNA duplex through one set of jaws, transport it through the cleaved first duplex, and expel it through the other set of jaws.
Acetylation, phosphorylation and methylation of the amino-terminal tails of histones are thought to be involved in the regulation of chromatin structure and function. With just one exception, the ...enzymes identified in the methylation of specific lysine residues on histones (histone methyltransferases) belong to the SET family. The high-resolution crystal structure of a ternary complex of human SET7/9 with a histone peptide and cofactor reveals that the peptide substrate and cofactor bind on opposite surfaces of the enzyme. The target lysine accesses the active site of the enzyme and the S-adenosyl-l-methionine (AdoMet) cofactor by inserting its side chain into a narrow channel that runs through the enzyme, connecting the two surfaces. Here we show from the structure and from solution studies that SET7/9, unlike most other SET proteins, is exclusively a mono-methylase. The structure indicates the molecular basis of the specificity of the enzyme for the histone target, and allows us to propose a model for the methylation reaction that accounts for the role of many of the residues that are invariant across the SET family.
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