Three‐Dimensional Solution Structure of Human Angiogenin Determined by 1H,15N‐NMR Spectroscopy — Characterisation of Histidine Protonation States and Pka Values

Lequin, Olivier; Thüring, Harald; Robin, Michel; Lallemand, Jean‐Yves

doi:10.1111/j.1432-1033.1997.00712.x

Cited by 38 publications

(50 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although RNase 3 is dimeric in the crystal, the protein fold determined by the two techniques is similar. In addition, NMR studies revealed two conformations for His114 of RNase 5 in solution [240]. The structures of RNase 2 and RNase 7 are given in Figure 4 (panels E and F).…”

Section: Three-dimensional Structures Of Human Antimicrobial Peptidesmentioning

confidence: 99%

Human Antimicrobial Peptides and Proteins

2014

View full text Add to dashboard Cite

As the key components of innate immunity, human host defense antimicrobial peptides and proteins (AMPs) play a critical role in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. This article provides an overview on the identification, activity, 3D structure, and mechanism of action of human AMPs selected from the antimicrobial peptide database. Over 100 such peptides have been identified from a variety of tissues and epithelial surfaces, including skin, eyes, ears, mouths, gut, immune, nervous and urinary systems. These peptides vary from 10 to 150 amino acids with a net charge between −3 and +20 and a hydrophobic content below 60%. The sequence diversity enables human AMPs to adopt various 3D structures and to attack pathogens by different mechanisms. While α-defensin HD-6 can self-assemble on the bacterial surface into nanonets to entangle bacteria, both HNP-1 and β-defensin hBD-3 are able to block cell wall biosynthesis by binding to lipid II. Lysozyme is well-characterized to cleave bacterial cell wall polysaccharides but can also kill bacteria by a non-catalytic mechanism. The two hydrophobic domains in the long amphipathic α-helix of human cathelicidin LL-37 lays the basis for binding and disrupting the curved anionic bacterial membrane surfaces by forming pores or via the carpet model. Furthermore, dermcidin may serve as ion channel by forming a long helix-bundle structure. In addition, the C-type lectin RegIIIα can initially recognize bacterial peptidoglycans followed by pore formation in the membrane. Finally, histatin 5 and GAPDH(2-32) can enter microbial cells to exert their effects. It appears that granulysin enters cells and kills intracellular pathogens with the aid of pore-forming perforin. This arsenal of human defense proteins not only keeps us healthy but also inspires the development of a new generation of personalized medicine to combat drug-resistant superbugs, fungi, viruses, parasites, or cancer. Alternatively, multiple factors (e.g., albumin, arginine, butyrate, calcium, cyclic AMP, isoleucine, short-chain fatty acids, UV B light, vitamin D, and zinc) are able to induce the expression of antimicrobial peptides, opening new avenues to the development of anti-infectious drugs.

show abstract

Section: Three-dimensional Structures Of Human Antimicrobial Peptidesmentioning

confidence: 99%

Human Antimicrobial Peptides and Proteins

2014

View full text Add to dashboard Cite

show abstract

“…NMR analysis revealed that human ANG is a relatively well-folded protein, with increased dynamics in some regions (e.g., backbone atoms of ~five residues at both N- and C-termini, and regions 59–70 and 82–95 were shown to possess relatively high root-mean square deviations from their position in the mean structure) [139]. Figure 3D shows that these regions are predicted to be intrinsically disordered.…”

Section: Illustrative Examples Of Idps In Neurodegenerationmentioning

confidence: 99%

Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D²concept

Uversky¹

2010

Expert Review of Proteomics

128

View full text Add to dashboard Cite

Many biologically active proteins, which are usually called intrinsically disordered or natively unfolded proteins, lack stable tertiary and/or secondary structure under physiological conditions in vitro. Their functions complement the functional repertoire of ordered proteins, with intrinsically disordered proteins (IDPs) often being involved in regulation, signaling and control. Their amino acid sequences and compositions are very different from those of ordered proteins, making reliable identification of IDPs possible at the proteome level. IDPs are highly abundant in various human diseases, including neurodegeneration and other protein dysfunction maladies and, therefore, represent attractive novel drug targets. Some of the aspects of IDPs, as well as their roles in neurodegeneration and protein dysfunction diseases, are discussed in this article, together with the peculiarities of IDPs as potential drug targets. Keywordsdisorder-based drug discovery; disorder prediction; intrinsically disordered protein; molten globule; premolten globule; random coil Intrinsically disordered proteinsProteins play a number of crucial roles in the maintenance of life, and protein dysfunctions may cause the development of various pathological conditions. For a very long time it has been believed that the specific functionality of a given protein is predetermined by its unique 3D structure [1,2]. However, Figure 1 shows that, although many proteins are indeed predisposed to fold into unique structures, which evolved to possess unique biological functions, some proteins can misfold either spontaneously or owing to a number of factors, such as mutations and other genetic alterations, problematic processing or post-translational modifications, or exposure to harmful environmental conditions. Such misfolding is now Tel.: +1 317 278, 6448 Fax: +1 317 278 9217, vuversky@iupui.edu. Financial & competing interests disclosure This work was supported in part by the Program of the Russian Academy of Sciences for the 'Molecular and cellular biology', by grants R01 LM007688-01A1 and GM071714-01A2 from the National Institutes of Health, and by the grant EF 0849803 from the National Science Foundation. I gratefully acknowledge the support of the IUPUI Signature Centers Initiative. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. NIH Public Access Author ManuscriptExpert Rev Proteomics. Author manuscript; available in PMC 2012 June 9. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript considered a crucial early step in the development of various protein conformation diseases [3]. Finally, many proteins (now widely known as intrinsically disordered proteins [IDPs]) possess no definite ordered 3D structure, but still play important biological roles...

show abstract

“… Schematic diagram of the subsites of the hAng active site. The residues shown were observed in various crystal and NMR structures to be within the sites …”

Section: Introductionmentioning

confidence: 96%

Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

et al. 2018

View full text Add to dashboard Cite

A member of the ribonuclease A superfamily, human angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced-fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modeling suggests the potential for simultaneous binding of the inhibitors at the active and cell-binding sites, NMR studies indicate greater affinity for the cell-binding site than for the active site. Additionally, molecular dynamics simulations at 100 ns confirmed the stability of binding at the cell-binding site with the predicted protein-ligand interactions, in excellent agreement with the NMR data. This is the first time that a nucleoside inhibitor is reported to completely inhibit the angiogenic activity of hAng in vivo by exerting dual inhibitory activity on hAng, blocking both the entrance of hAng into the cell and its ribonucleolytic activity.

show abstract

Three‐Dimensional Solution Structure of Human Angiogenin Determined by ¹H,¹⁵N‐NMR Spectroscopy — Characterisation of Histidine Protonation States and Pk_a Values

Cited by 38 publications

References 60 publications

Human Antimicrobial Peptides and Proteins

Human Antimicrobial Peptides and Proteins

Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D²concept

Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

Contact Info

Product

Resources

About

Three‐Dimensional Solution Structure of Human Angiogenin Determined by 1H,15N‐NMR Spectroscopy — Characterisation of Histidine Protonation States and Pka Values

Cited by 38 publications

References 60 publications

Human Antimicrobial Peptides and Proteins

Human Antimicrobial Peptides and Proteins

Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D2concept

Evidence for Novel Action at the Cell‐Binding Site of Human Angiogenin Revealed by Heteronuclear NMR Spectroscopy, in silico and in vivo Studies

Contact Info

Product

Resources

About

Three‐Dimensional Solution Structure of Human Angiogenin Determined by ¹H,¹⁵N‐NMR Spectroscopy — Characterisation of Histidine Protonation States and Pk_a Values

Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D²concept