C11orf54 catalyzes L-xylulose formation in human metabolism.

Excretion of L-xylulose is the hallmark of pentosuria, the fourth of Garrod's inborn errors of metabolism, yet the molecular basis for L-xylulose formation remains unknown. Here, by projecting coevolutionary data for 511,114 orthogroups across 1,929 eukaryotic genomes onto metabolic maps, we screen for unmapped genes in human metabolism. Among these, we show that the DUF1907 domain of C11orf54 catalyzes formation of L-xylulose by establishing a zinc-coordinated Michaelis complex with β-keto-L-gulonate (BKG).

The C-terminal PHDVC5HCH tandem domain of NSD2 is a combinatorial reader of unmodified H3K4 and tri-methylated H3K27 that regulates transcription of cell adhesion genes in multiple myeloma.

Histone methyltransferase NSD2 (MMSET) overexpression in multiple myeloma (MM) patients plays an important role in the development of this disease subtype. Through the expansion of transcriptional activating H3K36me2 and the suppression of repressive H3K27me3 marks, NSD2 activates an aberrant set of genes that contribute to myeloma growth, adhesive and invasive activities. NSD2 transcriptional activity also depends on its non-catalytic domains, which facilitate its recruitment to chromatin through histone binding.

The acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12.

Chemokine heterodimers activate or dampen their cognate receptors during inflammation. The CXCL12 chemokine forms with the fully reduced (fr) alarmin HMGB1 a physiologically relevant heterocomplex (frHMGB1•CXCL12) that synergically promotes the inflammatory response elicited by the G-protein coupled receptor CXCR4. The molecular details of complex formation were still elusive.

Erratum: A tetracationic porphyrin with dual anti-prion activity.

[This corrects the article DOI: 10.1016/j.isci.

A tetracationic porphyrin with dual anti-prion activity.

Prions are deadly infectious agents made of PrP, a misfolded variant of the cellular prion protein (PrP) which self-propagates by inducing misfolding of native PrP. PrP can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective therapies. We identified Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of native PrP, eliciting a dual anti-prion effect.

A simple and robust nanosystem for photoacoustic imaging of bladder cancer based on α5β1-targeted gold nanorods.

Background: Early detection and removal of bladder cancer in patients is crucial to prevent tumor recurrence and progression. Because current imaging techniques may fail to detect small lesions of in situ carcinomas, patients with bladder cancer often relapse after initial diagnosis, thereby requiring frequent follow-up and treatments.

Results: In an attempt to obtain a sensitive and high-resolution imaging modality for bladder cancer, we have developed a photoacoustic imaging approach based on the use of PEGylated gold nanorods (GNRs) as a contrast agent, functionalized with the peptide cyclic [CphgisoDGRG] (Iso4), a selective ligand of α5β1 integrin expressed by bladder cancer cells.

Nizp1 is a specific NUP98-NSD1 functional interactor that regulates NUP98-NSD1-dependent oncogenic programs.

NSD1, NSD2 and NSD3 proteins constitute a family of histone 3 lysine 36 (H3K36) methyltransferases with similar domain architecture, but diversified activities, in part, dependent on their non-enzymatic domains. These domains, despite their high sequence identity, recruit the hosting proteins to different chromatin regions through the recognition of diverse epigenetic marks and/or associations to distinct interactors. In this sense, the PHDvC5HCH finger tandem domain represents a paradigmatic example of functional divergence within the NSD family.

Pamoic acid is an inhibitor of HMGB1·CXCL12 elicited chemotaxis and reduces inflammation in murine models of Pseudomonas aeruginosa pneumonia.

Background: High-mobility group box 1 protein (HMGB1) is an ubiquitous nuclear protein that once released in the extracellular space acts as a Damage Associated Molecular Pattern and promotes inflammation. HMGB1 is significantly elevated during Pseudomonas aeruginosa infections and has a clinical relevance in respiratory diseases such as Cystic Fibrosis (CF). Salicylates are HMGB1 inhibitors.

Solution Structure of the BPSL1445 Protein of Reveals the SYLF Domain Three-Dimensional Fold.

The SYLF domain is an evolutionary conserved protein domain with phosphatidylinositol binding ability, whose three-dimensional structure is unknown. Here, we present the solution structure and the dynamics characterization of the SYLF domain of the bacterial BPSL1445 protein. BPSL1445 is a seroreactive antigen and a diagnostic marker of , the etiological agent of melioidosis, a severe infectious disease in the tropics.

Halting the Spread of Herpes Simplex Virus-1: The Discovery of an Effective Dual αvβ6/αvβ8 Integrin Ligand.

Over recent years, αvβ6 and αvβ8 Arg-Gly-Asp (RGD) integrins have risen to prominence as interchangeable co-receptors for the cellular entry of herpes simplex virus-1 (HSV-1). In fact, the employment of subtype-specific integrin-neutralizing antibodies or gene-silencing siRNAs has emerged as a valuable strategy for impairing HSV infectivity. Here, we shift the focus to a more affordable pharmaceutical approach based on small RGD-containing cyclic pentapeptides.

small molecules targeting the finger-finger interaction between the histone lysine methyltransferase NSD1 and Nizp1 repressor.

PHD fingers are small chromatin binding domains, that alone or in tandem work as versatile interaction platforms for diversified activities, ranging from the decoding of the modification status of histone tails to the specific recognition of non-histone proteins. They play a crucial role in their host protein as mutations thereof cause several human malignancies. Thus, PHD fingers are starting to be considered as valuable pharmacological targets.

Discovery of 5,5'-Methylenedi-2,3-Cresotic Acid as a Potent Inhibitor of the Chemotactic Activity of the HMGB1·CXCL12 Heterocomplex Using Virtual Screening and NMR Validation.

HMGB1 is a key molecule that both triggers and sustains inflammation following infection or injury, and is involved in a large number of pathologies, including cancer. HMGB1 participates in the recruitment of inflammatory cells, forming a heterocomplex with the chemokine CXCL12 (HMGB1·CXCL12), thereby activating the G-protein coupled receptor CXCR4. Thus, identification of molecules that disrupt this heterocomplex can offer novel pharmacological opportunities to treat inflammation-related diseases.

A stapled chromogranin A-derived peptide is a potent dual ligand for integrins αvβ6 and αvβ8.

Combining 2D STD-NMR, computation, biochemical assays and click-chemistry, we have identified a chromogranin-A derived compound (5) that has high affinity and bi-selectivity for αvβ6 and αvβ8 integrins and is stable in microsomal preparations. 5 is suitable for nanoparticle functionalization and delivery to cancer cells, holding promise for diagnostic and/or therapeutic applications.

Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment.

Extracellular HMGB1 triggers inflammation following infection or injury and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex.

The N-Terminal Domain of NPHP1 Folds into a Monomeric Left-Handed Antiparallel Three-Stranded Coiled Coil with Anti-apoptotic Function.

Mutations in the gene, coding for human nephrocystin-1 (NPHP1), cause the autosomal recessive disease nephronophthisis, the most common cause of end-stage renal disease in children and adolescents. The function and structure of NPHP1 are still poorly characterized. NPHP1 presents a modular structure well in keeping with its role as an adaptor protein: it harbors an SH3 domain flanked by two glutamic acid-rich regions and a conserved C-terminal nephrocystin homology domain (NHD).

Probing the interaction of a quercetin bioconjugate with Bcl-2 in living human cancer cells with in-cell NMR spectroscopy.

In-cell NMR spectroscopy has emerged as a powerful technique for monitoring biomolecular interactions at an atomic level inside intact cells. However, current methodologies are inadequate at charting intracellular interactions of nonlabeled proteins and require their prior isotopic labeling. Herein, we describe for the first time the monitoring of the quercetin-alanine bioconjugate interaction with the nonlabeled antiapoptotic protein Bcl-2 inside living human cancer cells.

Succinimide-Based Conjugates Improve IsoDGR Cyclopeptide Affinity to αβ without Promoting Integrin Allosteric Activation.

The isoDGR sequence is an integrin-binding motif that has been successfully employed as a tumor-vasculature-homing molecule or for the targeted delivery of drugs and diagnostic agents to tumors. In this context, we previously demonstrated that cyclopeptide 2, the product of the conjugation of c(CGisoDGRG) (1) to 4-( N-maleimidomethyl)cyclohexane-1-carboxamide, can be successfully used as a tumor-homing ligand for nanodrug delivery to neoplastic tissues. Here, combining NMR, computational, and biochemical methods, we show that the succinimide ring contained in 2 contributes to stabilizing interactions with αβ, an integrin overexpressed in the tumor vasculature.

Integrating a prospective pilot trial and patient-derived xenografts to trace metabolic changes associated with acute myeloid leukemia.

Despite the considerable progress in understanding the molecular bases of acute myeloid leukemia (AML), new tools to link disease biology to the unpredictable patient clinical course are still needed. Herein, high-throughput metabolomics, combined with the other "-omics" disciplines, holds promise in identifying disease-specific and clinically relevant features.In this study, we took advantage of nuclear magnetic resonance (NMR) to trace AML-associated metabolic trajectory employing two complementary strategies.

Flexible vs Rigid Epitope Conformations for Diagnostic- and Vaccine-Oriented Applications: Novel Insights from the Burkholderia pseudomallei BPSL2765 Pal3 Epitope.

Peptides seldom retain stable conformations if separated from their native protein structure. In an immunological context, this potentially affects the development of selective peptide-based bioprobes and, from a vaccine perspective, poses inherent limits in the elicitation of cross-reactive antibodies by candidate epitopes. Here, a 1,4-disubstituted-1,2,3-triazole-mediated stapling strategy was used to stabilize the native α-helical fold of the Pal3 peptidic epitope from the protein antigen PalBp (BPSL2765) from Burkholderia pseudomallei, the etiological agent of melioidosis.

Structural basis for PHDVC5HCHNSD1-C2HRNizp1 interaction: implications for Sotos syndrome.

Sotos syndrome is an overgrowth syndrome caused by mutations within the functional domains ofNSD1 gene coding for NSD1, a multidomain protein regulating chromatin structure and gene expression. In particular, PHDVC5HCHNSD1 tandem domain, composed by a classical (PHDV) and an atypical (C5HCH) plant homeo-domain (PHD) finger, is target of several pathological missense-mutations. PHDVC5HCHNSD1 is also crucial for NSD1-dependent transcriptional regulation and interacts with the C2HR domain of transcriptional repressor Nizp1 (C2HRNizp1)in vitro To get molecular insights into the mechanisms dictating the patho-physiological relevance of the PHD finger tandem domain, we solved its solution structure and provided a structural rationale for the effects of seven Sotos syndrome point-mutations.

2-Deoxy-d-Glucose Ameliorates PKD Progression.

Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-d-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally.

Backbone and side-chain (1)H, (15)N, (13)C assignment and secondary structure of BPSL1445 from Burkholderia pseudomallei.

BPSL1445 is a lipoprotein produced by the Gram-negative bacterium Burkholderia pseudomallei (B. pseudomallei), the etiological agent of melioidosis. Immunodetection assays against sera patients using protein microarray suggest BPSL1445 involvement in melioidosis.

Structure-based design of a B cell antigen from B. pseudomallei.

Burkholderia pseudomallei is the etiological agent of melioidosis, a severe endemic disease in South-East Asia, causing septicemia and organ failure with high mortality rates. Current treatments and diagnostic approaches are largely ineffective. The development of new diagnostic tools and vaccines toward effective therapeutic opportunities against B.

Structure of human Sp140 PHD finger: an atypical fold interacting with Pin1.

Sp140 is a nuclear leukocyte-specific protein involved in primary biliary cirrhosis and a risk factor in chronic lymphocytic leukemia. The presence of several chromatin related modules such as plant homeodomain (PHD), bromodomain and SAND domain suggests a role in chromatin-mediated regulation of gene expression; however, its real function is still elusive. Herein we present the solution structure of Sp140-PHD finger and investigate its role as epigenetic reader in vitro.