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An action shot of the protein Scp1, which plays a crucial role in the development of the nervous system has been obtained using crystallography by researchers in the US. Their structure could provide drug designers with a template for creating small molecule inhibitors of this protein that would be useful in neurological research. Joseph Noel and Samuel Pfaff of the Salk Institute for Biological Studies and colleagues there and at the University of California, San Diego (UCSD) and The Scripps Research Institute, La Jolla explain that a network of signalling molecules controls embryonic stem cell differentiation. Controlling the controllers might allow scientists to nudge embryonic stem cells into becoming specific cell types, which would be useful in basic research and for potential therapies. "Scp1 is an important brake that regulates the transition from neuronal precursor to mature neuron," explains Noel, "Loosening the brake with an inhibitor would allow us to influence the timing of neuronal differentiation." Scp1 is a small carboxyl-terminal phosphatase (SCP) and is expressed in almost all tissues of the body. Its job is to prevent RNA polymerase II from reading and switching on neuronal genes inappropriately in various tissues, including skin, muscle and liver. In contrast, Scp1 is switched off in the nervous system enabling RNA polymerase II to express neuronal genes allowing stem cells to specialise into neurones. The researchers found that Scp1 hangs onto a seven amino acid sequence in the polymerase tail. "We captured Scp1 bound to a single seven amino-acid long repeat containing specific phosphates," explains team member Yan Zhang, "It turns out that only three amino acids are important for Scp1's ability to know how to remove phosphates from RNA polymerase." She adds that knowing how enzymes like Scp1 precisely recognize that seven amino acid stretch is exactly the kind of "unambiguous information relevant for the design of a chemical inhibitor by a process known as structure-based drug design." The team has already begun the search, having designed the first generation of inhibitors for synthesising and testing. Related links:
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