Obesity and type II diabetes are closely linked metabolic syndromes that afflict >100 million people worldwide. Although protein tyrosine phosphatase 1B (PTP1B) has emerged as a promising target for the treatment of both syndromes, the discovery of pharmaceutically acceptable inhibitors that bind at the active site remains a substantial challenge. Here we describe the discovery of an allosteric site in PTP1B. Crystal structures of PTP1B in complex with allosteric inhibitors reveal a novel site located approximately 20 A from the catalytic site. We show that allosteric inhibitors prevent formation of the active form of the enzyme by blocking mobility of the catalytic loop, thereby exploiting a general mechanism used by tyrosine phosphatases. Notably, these inhibitors exhibit selectivity for PTP1B and enhance insulin signaling in cells. Allosteric inhibition is a promising strategy for targeting PTP1B and constitutes a mechanism that may be applicable to other tyrosine phosphatases.

The small molecule binds to the same site that binds the IL-2 ␣ receptor and buries into a groove not seen in the free structure of IL-2. Comparison of the bound and several free structures shows this site to be composed of two subsites: one is rigid, and the other is highly adaptive. Thermodynamic data suggest the energy barriers between these conformations are low. The subsites were dissected by using a site-directed screening method called tethering, in which small fragments were captured by disulfide interchange with cysteines introduced into IL-2 around these subsites. X-ray structures with the tethered fragments show that the subsite-binding interactions are similar to those observed with the original small molecule. Moreover, the adaptive subsite tethered many more compounds than did the rigid one. Thus, the adaptive nature of a protein-protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface.

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A method has been developed for monitoring the film-forming properties of antiwear additives in rolling-sliding, lubricated contacts. This makes it possible to study both the kinetics of reaction film growth and also the evolution of the film morphology as a function of rubbing time. The technique has been applied to investigate the behavior of a zinc dialhyl-dithiophosphate (ZDDP) additive sollrtion and to correlate this with simultaneous friction and wear measurements.The results show that ZDDP fonrzs a thick, solid-like, reaction film in the rubbing tracks, with negligible film growth outside of the truck. This film is extremely effective in preventing metalmetal contact. However the film is unevenly-distributed, with its roughness oriented in the direction of sliding. This directional roughness inhibits the entrainment offluidfilm in the mixed lubrication regime, increases the proportion of load supported by solid-solid contact and corlseqrrently results in the high friction often associated with the use of ZDDP additives. INTRODUCTIONZinc dialkyldithiophosphate (ZDDP) has been the principal antiwear additive used in engine oil formulations for many years. Despite a great deal of research effort, it is still not fully understand how this additive reduces wear. It is known that ZDDPs form reaction films on rubbing metal surfaces, and the composition and properties of these films has been analyzed using a range of surface chemical techniques. However relatively little is known about the thickness, distribution and kinetics of formation and removal of the films formed.In recent years, the need to understand clearly how ZDDPs function has been reinforced by two new factors. One is a need to develop lubricants which minimize friction in engines and thus reduce energy consumption. It has been found that some ZDDP formulations can produce an undesirable increase in friction in thin film lubrication conditions, and it is important to understand the origins of this (I). Secondly, environmental concerns have resulted in reduction in the ash and phosphorus content of engine oils, both to reduce emissions and to help preserve catalyst life. ZDDP is a saurce of both ash and phosphorus, so there is a progressive trend towards its partial or total substitution by ash-free and/or phosphorus-free antiwear additives. Paradoxically, the search for satisfactory alternatives to ZDDPs strengthens the need to have a good understanding of how the latter behaves.In the current paper, a new experimental technique is described for studying antiwear films on rubbing surfaces. This technique is used, in conjunction with friction measurements, to determine the distribution of the antiwear films formed by ZDDP and to elucidate the origins of the effect of the additive on friction. BACKGROUND

Five pharmaceutical materials, including two salts and three neutral compounds, have been subjected to nanoindentation analysis on a single-crystal scale. The nanoindentation experiments were used to calculate a brittleness index for each of the five materials. These results were compared to the size reductions that were obtained on a pilot-plant scale mill. A good correlation between single crystal and large pilot-plant scale results was obtained for the range of materials studied.