Designing dual inhibitors of Mdm2/MdmX: Unexpected coupling of water with gatekeeper Y100/99

Mdm2 and MdmX share high structural similarity in their N-terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99.

type: 
Journal Paper
Url: 
http://onlinelibrary.wiley.com/doi/10.1002/prot.25310/abstract
Impact Factor: 
2.289
Date of acceptance: 
2017-04-17

Modeling the Structure of Keratin 1 and 10 Terminal Domains and their Misassembly in Keratoderma

The terminal domains of suprabasal keratins of the skin epithelium are very resistant to evidence-based structural analysis because of their inherent flexibility and lack of predictable structure. We present a model for the structure and interactions of the head and tail domains of epidermal keratins 1 and 10, based on all-atom 3D simulations of keratin primary amino acid sequences, and tyrosine phosphorylation predictions, extracted from published databases.

type: 
Journal Paper
journal: 
Journal of Investigative Dermatology, 2017 May 16. pii: S0022-202X(17)31522-1. doi: 10.1016/j.jid.2017.03.038
pubmed: 
28526297
Url: 
https://www.ncbi.nlm.nih.gov/pubmed/?term=28526297
Impact Factor: 
6.287
Date of acceptance: 
2017-03-20

Hydration effects on the efficacy of the Epidermal growth factor receptor kinase inhibitor afatinib

Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket.

type: 
Journal Paper
journal: 
Scientific Reports 7, Article no: 1540 (2017), doi:10.1038/s41598-017-01491-z
Url: 
https://www.nature.com/articles/s41598-017-01491-z?WT.feed_name=subjects_biophysics
Impact Factor: 
4.259
Date of acceptance: 
2017-03-28

Aggregation of thrombin-derived C-terminal fragments as a previously undisclosed host defense mechanism

Effective control of endotoxins and bacteria is crucial for normal wound healing. During injury, the key enzyme thrombin is formed, leading to generation of fibrin. Here, we show that human neutrophil elastase cleaves thrombin, generating 11-kDa thrombin-derived C-terminal peptides (TCPs), which bind to and form amorphous amyloid-like aggregates with both bacterial lipopolysaccharide (LPS) and gram-negative bacteria.

type: 
Journal Paper
journal: 
Proceedings of the National Academy of Sciences (PNAS), May 4, 2017, doi: 10.1073/pnas.1619609114
pubmed: 
28362432
Url: 
http://www.pnas.org/content/early/2017/05/03/1619609114.abstract
Impact Factor: 
9.661
Date of acceptance: 
2017-05-12

Progress in Molecular Dynamics Simulations of Bacterial Cell Envelopes

Bacteria are protected by complex molecular architectures known as the cell envelope. The cell envelope is composed of regions with distinct chemical compositions and physical properties, namely, membranes and a cell wall. To develop novel antibiotics to combat pathogenic bacteria, molecular level knowledge of the structure, dynamics, and interplay between the chemical components of the cell envelope that surrounds bacterial cells is imperative.

type: 
Journal Paper
journal: 
The Journal of Physical Chemistry Letters, 2017 Jun 1;8(11):2513-2518. doi: 10.1021/acs.jpclett.7b00473
pubmed: 
28467715
Url: 
https://www.ncbi.nlm.nih.gov/pubmed/28467715
Impact Factor: 
9.353
Date of acceptance: 
2017-05-03

Full-length, Oligomeric Structure of Wzz Determined by Cryoelectron Microscopy Reveals Insights into Membrane-Bound States

Wzz is an integral inner membrane protein involved in regulating the length of lipopolysaccharide O-antigen glycans and essential for the virulence of many Gram-negative pathogens. In all Wzz homologs, the large periplasmic domain is proposed to be anchored by two transmembrane helices, but no information is available for the transmembrane and cytosolic domains. Here we have studied purified oligomeric Wzz complexes using cryoelectron microscopy and resolved the transmembrane regions within a semi-continuous detergent micelle.

type: 
Journal Paper
journal: 
Structure, 2017 May 2;25(5):806-815. e3. doi: 10.1016/j.str.2017.03.017
pubmed: 
28434914
Url: 
https://www.ncbi.nlm.nih.gov/pubmed/28434914
Impact Factor: 
5.618

Cross-reactive dengue human monoclonal antibody prevents severe pathologies and death from Zika virus infections

Zika virus (ZIKV) infections have been linked with neurological complications and congenital Zika syndrome. Given the high level of homology between ZIKV and the related flavivirus dengue virus (DENV), we investigated the level of cross-reactivity with ZIKV using a panel of DENV human mAbs. A majority of the mAbs showed binding to ZIKV virions, with several exhibiting neutralizing capacities against ZIKV in vitro. Three of the best ZIKV-neutralizing mAbs were found to recognize diverse epitopes on the envelope (E) glycoprotein: the highly conserved fusion-loop peptide, a

type: 
Journal Paper
journal: 
JCI Insight. 2017 Apr 20;2(8). pii: 92428. doi: 10.1172/jci.insight.92428
Url: 
https://insight.jci.org/articles/view/92428
Date of acceptance: 
2017-04-21

Polar N-terminal Residues Conserved in Type 2 Secretion Pseudopilins Determine Subunit Targeting and Membrane Extraction Steps during Fibre Assembly

Bacterial type 2 secretion systems (T2SS), type 4 pili, and archaeal flagella assemble fibres from initially membrane-embedded pseudopilin and pilin subunits. Fibre subunits are made as precursors with positively charged N-terminal anchors, whose cleavage via the prepilin peptidase, essential for pilin membrane extraction and assembly, is followed by N-methylation of the mature (pseudo)pilin N terminus. The conserved Glu residue at position 5 (E5) of mature (pseudo)pilins is essential for assembly.

type: 
Journal Paper
journal: 
Journal of Molecular Biology, Vol. 429, Issue 11, 2 Jun 2017, Pg 1746-1765
pubmed: 
28427876
Url: 
https://www.ncbi.nlm.nih.gov/pubmed/?term=28427876
Impact Factor: 
4.333

Quantitative 3D analysis of complex single border cell behaviors in coordinated collective cell migration

Understanding the mechanisms of collective cell migration is crucial for cancer metastasis, wound healing and many developmental processes. Imaging a migrating cluster in vivo is feasible, but the quantification of individual cell behaviours remains challenging. We have developed an image analysis toolkit, CCMToolKit, to quantify the Drosophila border cell system. In addition to chaotic motion, previous studies reported that the migrating cells are able to migrate in a highly coordinated pattern.

type: 
Journal Paper
journal: 
Nature Communications, 2017 Apr 4;8:14905. doi: 10.1038/ncomms14905
pubmed: 
28374738
Url: 
https://www.nature.com/articles/ncomms14905
Impact Factor: 
12.124
Date of acceptance: 
2017-02-10

Regulation of Transcriptional Activators by DNA-Binding Domain Ubiquitination

Ubiquitin is a key component of the regulatory network that maintains gene expression in eukaryotes, yet the molecular mechanism(s) by which non-degradative ubiquitination modulates transcriptional activator (TA) function is unknown. Here endogenous p53, a stress-activated transcription factor required to maintain health, is stably monoubiquitinated, following pathway activation by IR or Nutlin-3 and localized to the nucleus where it becomes tightly associated with chromatin.

type: 
Journal Paper
journal: 
Cell Death and Differentiation 2017 May;24(5):903-916. doi: 10.1038/cdd.2017.42
pubmed: 
, PMID: 28362432
Url: 
https://www.ncbi.nlm.nih.gov/pubmed/28362432
Impact Factor: 
8.218
Date of acceptance: 
2017-02-16
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