Elkins looked at me. There was another famous BBC occasion in This time Elkins, for once, got the story wrong. The Israeli army had invaded Lebanon and surrounded Beirut. When the Phalangist militia belonging to their Lebanese allies, the Maronite Christians, began a brutal massacre of Palestinians and other Muslims in the Sabra and Shatilla refugee camps, Israeli troops simply looked the other way. Back in Jerusalem, Elkins was, at first, misled by Israeli sources. His BBC report was inaccurate.
I was in Beirut at that time. I heard the comments of French correspondents in my hotel. The next morning, Elkins was on the World Service again. He had been duped, his voice was bristling with anger, his underlining of Israeli complicity now trenchant. By chance, I overheard the same French group again, this time at the breakfast table. He was indeed a phenomenon, a man of parts. Born to European immigrants to the United States, he grew up in New York, and was top of the class in almost everything at school, especially English - he had an inspiring teacher.
Then, as a youngster, he fell in with hoodlums, but later went west to join his elder brother, Saul, a Hollywood producer. There, Elkins the film script-writer and trade-union organiser was born. Over the years, he scripted more than 30 Hollywood B-movies. His work as a union representative got him blacklisted by the House UnAmerican Activities Committee, who accused him falsely of being a communist.
He was no communist, but was certainly an active anti-fascist before the second world war, a supporter of the International Brigades in republican Spain. With the war, Elkins was recruited into a shadowy, clandestine world. He was dispatched on murky missions behind enemy lines in Europe. Heaven knows what these involved. Certainly, he was with US troops when the Dachau death camp was liberated. And it was with this experience, encountering skeletal Holocaust survivors, that Elkins rediscovered his own Jewish roots.
In his book, Forged In Fury, published in , Elkins wrote of a secret Jewish organisation, some strong, called DIN, formed in Europe in to assassinate "the killers of Jews" - former Nazis, SS men, camp staff and others who had slipped away unpunished into civilian life. DIN was shortlived but deadly. Elkins changed names, places and dates to protect those of whom he wrote. Kollek was masterminding illegal shipments of arms to the Jewish Haganah in Palestine. With his OSS experience, Elkins was soon on board.
When he found the FBI on his tail, he and his wife, Martha, decamped in a hurry to the new-born state of Israel. After living for a year on a kibbutz, he took up documentary film-making, before getting into journalism, first with CBS and Newsweek, then, in , with the BBC.
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The combined observations of the dimerisation interface that stabilizes the bound, unphosphorylated, hydrophobic motif, and the active conformation of the unphosphorylated activation loop suggest that DMPK does not require phosphorylation for activation. This has also been proposed for the ROCKs. Although DMPK is active without phosphorylation, there is still the question of what the structural impact of phosphorylation at the conserved phosphorylation sites would be, if indeed they do get phosphorylated. With regard to potential kinases that phosphorylate DMPK, a known example is Raf-1 kinase which can bind to DMPK and also phosphorylate it, stimulating both its auto-phosphorylation and trans-phosphorylation activity.
The arginine of the HRD motif that would bind such a phosphorylation is present, but taken together with the activated position of the activation loop in the absence of phosphorylation, this suggests that phosphorylation of the activation loop may not increase the activity of DMPK.
Hydrophobic interactions on both faces of the inhibitor provide the majority of the binding interactions.
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The only difference is in the position of the primary amine. The resulting plasmid was transformed into E. When the OD reached 0. Expression was continued overnight before the cells were harvested by centrifugation. The cells were resuspended in binding buffer 50 m M Hepes pH 7. The resuspended cells were thawed, lysed by sonication, and the cell debris was removed by centrifugation.
The DMPK1 protein was purified from the clarified cell lysate by immobilized metal ion chromatography followed by size-exclusion chromatography: Crystals appeared after a few weeks. X-ray data was collected at the Swiss Light Source beamline X10 using a cryostream to maintain the crystal at K. There were two molecules in the asymmetric unit of a P 3 2 21 unit cell. Sedimentation of particles was monitored using the interference optics in a Beckman XL-I Analytical Ultracentrifuge equipped with a Ti rotor.
The BIM compounds were originally designed to be more effective, and also more selective, versions of the general kinase inhibitor staurosporine, as well as providing access to a range of synthetically accessible derivatives of the basic scaffold and allowing flexibility between the indole rings.
For many protein kinases it is desirable to be able to have specific inhibitors, however for DMPK it seems more likely that avoidance of inhibition is the aim. Nevertheless, inhibitor design for drug targets in the AGC family of kinases is aided by additional structural knowledge of this family.
The structure of DMPK illustrates that the most structurally varied part of AGC kinase proteins is the long C-terminus; compared with the structure of the closely related ROCKs, this is the only region of substantial structural divergence. Furthermore, the difference in the location of the conserved C-terminal NFD motif, adjacent to the active site in the ROCKs and away from it in DMPK, can be compared with the similarity in position of the only partially conserved C-terminal turn motif. In designing specific inhibitors for AGC family kinases, it may be necessary to incorporate the C-terminus into the design.
Inhibitors that can occupy the ATP-binding site while also offering moieties capable of binding divergent motifs on the C-terminal extension may be a worthwhile future direction. Coordinates and structure factors have been deposited in the Protein Data Bank with the accession code 2VD5. The authors thank Frank von Delft and members of the SGC crystallography group for assistance with X-ray data collection. National Center for Biotechnology Information , U.
Journal List Protein Sci v. Published online Feb Author information Article notes Copyright and License information Disclaimer. Stefan Knapp or Jonathan M.
Group Leader - Kinases
This article has been cited by other articles in PMC. Introduction Dystrophia myotonica protein kinase DMPK is a protein strongly linked to myotonic dystrophy type 1 DM1 , the most prevalent muscular dystrophy in adults. Results and Discussion The DMPK structure shows the typical fold of a protein kinase, with two lobes connected by a hinge region see Fig. Open in a separate window.
Conserved dimerisation domain The crystallographic asymmetric unit contains two molecules of the DMPK kinase domain. Conserved binding of the C-terminal tail to the N-terminal lobe - the hydrophobic motif The dimerization interface is made possible by the binding of the C-terminal tail of the kinase domain to a groove in the N-terminal lobe see Fig. Active conformation despite lack of phosphorylation Mass spectrometry of the recombinant DMPK confirmed that the crystallized protein was unphosphorylated.
Table 1 Data Collection and Refinement Statistics. Conclusions The BIM compounds were originally designed to be more effective, and also more selective, versions of the general kinase inhibitor staurosporine, as well as providing access to a range of synthetically accessible derivatives of the basic scaffold and allowing flexibility between the indole rings. Coordinates Coordinates and structure factors have been deposited in the Protein Data Bank with the accession code 2VD5.
Acknowledgments The authors thank Frank von Delft and members of the SGC crystallography group for assistance with X-ray data collection. Am J Hum Genet. RNA pathogenesis of the myotonic dystrophies. Wansink DG, Wieringa B. Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Recruitment of human muscleblind proteins to CUG n expansions associated with myotonic dystrophy. DM1 CTG expansions affect insulin receptor isoforms expression in various tissues of transgenic mice.
Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy. DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model. Role of myotonic dystrophy protein kinase DMPK in glucose homeostasis and muscle insulin action. Phospholemman is a substrate for myotonic dystrophy protein kinase. Myotonic dystrophy protein kinase phosphorylates the myosin phosphatase targetting subunit and inhibits myosin phosphatase activity.
Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum. Constitutive and regulated modes of splicing produce six major myotonic dystrophy protein kinase DMPK isoforms with distinct properties. Molecular insights into the self-assembly mechanism of dystrophia myotonica kinase. New insights into the structure-function relationships of Rho-associated kinase: The structure of dimeric ROCK1 reveals the mechanism for ligand selectivity.
Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil. Alternative splicing controls myotonic dystrophy protein kinase structure, enzymatic activity, and subcellular localization. The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module.