Poly(ADP-ribose) polymerase (PARP) inhibitors have been rapidly integrated into clinical practice for women with ovarian cancer. Currently, PARP inhibitors are approved as frontline maintenance treatment for patients with and without BRCA-associated cancers, and they are listed by the National Comprehensive Cancer Network (NCCN) as a treatment option for all high-grade serous and endometrioid cancers with or without bevacizumab. PARP inhibitors are also approved as maintenance treatment following a response to platinum-based therapy in the recurrent setting, irrespective of biomarker status. Additionally, PARP inhibitors are approved as third-line treatment and beyond in lieu of chemotherapy for patients with BRCA-associated cancers, and as fourth-line treatment and beyond for patients with platinum-sensitive homologous recombination-deficient tumors. They are also listed by the NCCN in combination with bevacizumab for the treatment of patients who have platinum-sensitive recurrent disease. The first part of this 2-part review focuses on the changing paradigm of frontline therapy options resulting from the recent approvals of PARP inhibitors; the second part considers the role of PARP inhibition in recurrent ovarian cancer.Interactions between a protein and a peptide motif of its protein partner are prevalent in nature. Often, a protein also has multiple interaction partners. X-ray protein crystallography is commonly used to examine these interactions in terms of bond distances and angles as well as to describe hotspots within protein complexes. However, the crystallization process presents a significant bottleneck in structure determination since it often requires notably time-consuming screening procedures, which involve testing a broad range of crystallization conditions via a trial-and-error approach. This difficulty is also increased as each protein-peptide complex does not necessarily crystallize under the same conditions. Here, a new co-crystallization/peptide-soaking method is presented which circumvents the need to return to the initial lengthy crystal screening and optimization processes for each consequent new complex. The 14-3-3σ protein, which has multiple interacting partners with specific peptidic motifs, was used as a case study. It was found that co-crystals of 14-3-3σ and a low-affinity peptide from one of its partners, c-Jun, could easily be soaked with another interacting peptide to quickly and easily generate new structures at high resolution. Not only does this significantly reduce the production time, but new 14-3-3-peptide structures that were previously not accessible with the 14-3-3σ isoform, despite screening hundreds of other different conditions, were now also able to be resolved. The findings achieved in this study may be considered as a supporting and practical guide to potentially enable the acceleration of the crystallization process of any protein-peptide system.The malaria parasite Plasmodium falciparum extensively modifies erythrocytes that it invades by exporting a large complement of proteins to the host cell. Among these exported components is a single heat-shock 70 kDa class protein, PfHsp70-x, that supports the virulence and growth rate of the parasite during febrile episodes. The ATP-binding domain of PfHsp70-x has previously been resolved and showed the presence of potentially druggable epitopes that differ from those on human Hsp70 chaperones. Here, the crystallographic structure of the substrate-binding domain (SBD) of PfHsp70-x is presented in complex with a hydrophobic peptide. The PfHsp70-x SBD is shown to be highly similar to the counterpart from a human erythrocytic Hsp70 chaperone. The binding of substrate at the interface between β-sandwich and α-helical subdomains of this chaperone segment is also conserved between the malaria parasite and humans. It is hypothesized that the parasite may partly exploit human chaperones for intra-erythrocytic trafficking and maintenance of its exported proteome.LonA peptidase is a major component of the protein quality-control mechanism in both prokaryotes and the organelles of eukaryotes. Proteins homologous to the N-terminal domain of LonA peptidase, but lacking its other domains, are conserved in several phyla of prokaryotes, including the Xanthomonadales order. However, the function of these homologous proteins (LonNTD-like proteins) is not known. Here, the crystal structure of the LonNTD-like protein from Xanthomonas campestris (XCC3289; UniProt Q8P5P7) is reported at 2.8 Å resolution. The structure was solved by molecular replacement and contains one polypeptide in the asymmetric unit. The structure was refined to an Rfree of 29%. The structure of XCC3289 consists of two domains joined by a long loop. The N-terminal domain (residues 1-112) consists of an α-helix surrounded by β-sheets, whereas the C-terminal domain (residues 123-193) is an α-helical bundle.  https://www.selleckchem.com/products/pepstatin-a.html  The fold and spatial orientation of the two domains closely resembles those of the N-terminal domains of the LonA peptidases from Escherichia coli and Mycobacterium avium. The structure is also similar to that of cereblon, a substrate-recognizing component of the E3 ubiquitin ligase complex. The N-terminal domains of both LonA and cereblon are known to be involved in specific protein-protein interactions. This structural analysis suggests that XCC3289 and other LonNTD-like proteins might also be capable of such protein-protein interactions.The replication of SARS-CoV-2 produces two large polyproteins, pp1a and pp1ab, that are inactive until cleavage by the viral chymotrypsin-like cysteine protease enzyme (3CL Mpro) into a series of smaller functional proteins. At the heart of 3CL Mpro is an unusual catalytic dyad formed by the side chains of His41 and Cys145 and a coordinated water molecule. The catalytic mechanism by which the enzyme operates is still unknown, as crucial information on the protonation states within the active site is unclear. To experimentally determine the protonation states of the catalytic site and of the other residues in the substrate-binding cavity, and to visualize the hydrogen-bonding networks throughout the enzyme, room-temperature neutron and X-ray data were collected from a large H/D-exchanged crystal of ligand-free (apo) 3CL Mpro.