UK Research Team First to Map Structures of Single Transporter Protein
A team of researchers from the Universities of Leeds, Oxford and Imperial College London have captured the 3D atomic models of a single transporter protein in each of its three main structural states, a goal of researchers from around the world for over 25 years. The discovery offers remarkable insight into the function of one of the body’s most fundamental processes – the movement of essential chemicals into cells of the body - and creates the opportunity to develop brand new drugs.
Biologists have surmised that transporter proteins of this type, which sit in the cell membrane, carry molecules through the otherwise impermeable membrane by shifting between at least three distinct structural states, controlled by ion gradients. In the first state, there is an outward-facing cavity. A compound will enter this cavity and attach to a binding site whereupon the protein will move to a second state with the cargo locked inside. The third state is formed when the protein opens up a cavity on the inward-facing side to release the compound into the cell. The switch between outward and inward-facing sides works rather like a ‘kissing gate’ in which the cavity is either on one side or the other but there is never a direct channel through the protein.
However, until now, scientists had never observed the structural details of these three states in a single protein and theories about how the mechanism worked in detail were based on stitching together their observations from different transporters.
“Previous models gave us a broad understanding of the mechanism involved, but this could never really be usefully applied for drug development,” said Professor Peter Henderson of the University of Leeds. “The goal for researchers in this area has always been to observe the entire mechanism in a single protein.”
The research [1] reports the mapping of the inward-facing structure of the bacterial Mhp1 transporter protein, the third structural state that they have determined for this protein. The team has been studying Mhp1 for more than ten years and their observations of the first two structures were published in Science in October 2008.
The protein was produced in Leeds; the structures were determined by X-ray crystallography and analysed at Imperial College and the Imperial College Membrane Protein Laboratory (MPL) located at Diamond Light Source. To further investigate the transitions between the three states of the protein dynamic molecular simulations were carried out at Oxford University.
“This third structure completes the picture and we can now understand Mhp1’s ‘alternating access’ mechanism in great detail,” said Dr Alexander Cameron, from the Division of Molecular Biosciences at Imperial College London. “We also unexpectedly found that the structures are similar across many transporter proteins previously thought to be different, so we’re expecting our model to help achieve some rapid progress in the research of colleagues around the world.”
The detailed knowledge of the mechanism could unlock new drug developments in several ways, said Professor Henderson. “Altering the delivery of compounds into a cell is one potential benefit for treating illness. For example, this could be useful in treating conditions where certain chemicals are lacking and need boosting permanently - such as serotonin for those suffering from depression and glucose for those with diabetes.”
The mechanism’s detail is already being used by chemists in the EU- funded European Drug Initiative on Channels and Transporters consortium (EDICT), which Professor Henderson leads. “We’ve found around 20 compounds that match Mhp1’s binding site, and of these, three have been shown to bind. I think we are entering an exciting period of discovery.”
“It’s taken a long time to get to this point – over ten years – but then difficult science takes time. This is the point at which blue skies research evolves into useful applications,” said Professor Henderson. “It’s the best thing I’ve been involved in during my academic career.”
Funded by the Biotechnology and Biological Sciences Research Council (BBSRC), the EU, the Japanese Science and Technology Agency and the Wellcome Trust, the research team comprises: Professor Henderson and colleagues from Leeds, who expressed and purified the Mhp1 protein; Professor So Iwata, Dr Alex Cameron and colleagues from Imperial College London and the MPL who imaged the crystals and combined all the information to propose a mechanism for the alternating access model; and Professor Mark Sansom and Dr Oliver Beckstein from the University of Oxford who authenticated the plausibility of the transitions between the three states.
Professor Henderson says that the next step is to investigate what triggers the protein to change between the states and the team has secured further funding from BBSRC and the EDICT consortium to pursue this.
[1]. Molecular Basis of Alternating Access Membrane Transport by the Sodium-Hydantoin Transporter Mhp1, Science, 23 April 2010.
TO FIND OUT MORE CIRCLE NO. Pioneer in Nanoscience Research Visits Jeol USA
World renowned physicist Dr Sumio Iijima, who pioneered the use of high resolution transmission electron microscopy (HRTEM) to characterise nanomaterials in the early ’70s and who also successfully imaged carbon nanotubes in the early ‘90s visited Jeol USA last month following a speaking engagement at MIT’s Center for Materials Science and Engineering.
Dr Iijima’s accomplishments are many, beginning with his groundbreaking work at Arizona State University and later at the Research Development Corporation of Japan and at NEC. He produced the first atomic resolution micrographs with the HRTEM, characterised the structure of crystalline solids and imaged small clusters in the structure of gold particles. He looked at short-range order in carbon specimens and his micrographs validated the structure of C60. In 1991, he published a paper on the crystalline structure of carbon nanotubes.
The discovery of carbon nanotubes has fueled intense research in nanoscience and transformed knowledge of materials that are developed to benefit society. “Science is always looking for something new,” Dr Iijima mused. “Like the discovery of the transistor, small things become giant and the seeds begin to grow.”
Iijima admits to always thinking of microscopy as a hobby – not a job - and his instruments of choice are the TEM, and, when not investigating nanomaterials, the flute.
“We’re honoured to have such a distinguished leader in the field of nanoscience visit with us,” said Bob Santorelli, CEO of JEOL USA, who hosted the visit along with Shinichi Watanabe, Chairman; Peter Genovese, President; and Hisao Wada, Vice President.
Dr Iijima was recently honoured as a guest of the Emperor and Empress of Japan, and was presented with the 2009 Order of Culture award for materials science.
Iijima has also received the prestigious Kavli prize in 2008, Spain’s 2008 Prince of Asturias Award, and the 2007 Balzan Prize for Nanoscience. He was elected as a US foreign member of the U.S.
National Academy of Science in 2007, and received the 2002 Benjamin Franklin Medal in Physics. Iijima is currently a Professor at Meijo University, Director of the AIST/Nanotube Research Center, Senior Research Fellow at NEC, and Dean of Sungkyunkwan Advanced Institute of Nanotechnology in Seoul, Korea.
(L to R) Peter Genovese, JEOL USA President; Hisao Wada, Vice President; Dr Sumio Iijima; Bob Santorelli, CEO; and Shinichi Watanabe, Chairman.
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Workshop Attracts High Numbers
A recent workshop on aberration corrected electron microscopy held at Harvard University and sponsored by Carl Zeiss, attracted an unexpectedly high audience, requiring the organisers to move around 100 attendees to a much larger lecture hall than originally planned. Professor Frans Spaepen, Interim Director of the CNS (Center for Nanoscale Systems) said: “The workshop on aberration- corrected electron microscopy at CNS was a great success. It was the culmination point of our collaboration with Carl Zeiss to bring electron microscopy at Harvard to the leading edge. The Workshop featured highly instructive and forward-looking talks by the foremost experts in aberration correction, including several from Carl Zeiss, as well as hands-on demonstrations the next day. I was very pleased with the interest from both inside and outside Harvard, and I thank the scientists, engineers and managers at Carl Zeiss for helping to make this possible.”
On the first day, internationally renowned experts in the field gave lectures on the background, theory, implementation and applications of aberration correction in TEM and STEM. The second day focused on seminars, discussion meetings and student tutorials on the two newly installed ZEISS Libra 200 Monochromated Aberration Corrected Electron Microscopes at Harvard University. These are located in the Center for Nanoscale Systems.
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Fostering Scientific Links Between the UK and Japan
University of Nottingham scientists are to collaborate with their counterparts at two leading Japanese universities in the search for a better understanding of
E.coli, a prevalent bug which can be fatal. Dr Dov Stekel and Dr Jon Hobman have won a £23,000 Japan Partnering Award from the Biotechnology and Biological Sciences Research Council (BBSRC), a prestigious award set up to bring together leading researchers and foster long-term relationships between the UK and Japan.
Dr Stekel and Dr Hobman will collaborate with research teams led by Professors Naotake Ogasawara and Shigehiko Kanaya at the Nara Institute of Science and Technology, and Dr Toru Tobe at the University of Osaka.
E.coli is a species of bacterium found in the intestines of animals and humans. Some strains can survive ingestion and establish themselves in the gut, causing infection and a variety of diseases including cystitis, meningitis and diarrhoea.
E.coli is usually transferred to humans by ingesting contaminated water, or contaminated food, such as meat, which has not been cooked properly. Variants such as the 0157 strain are potentially fatal. In the UK’s worst recorded outbreak, 20 people died over a period of weeks in 1996-7 after attending a church lunch in Strathclyde, Scotland.
Dr Stekel, Associate Professor of Integrative Systems Biology, in the School of Biosciences, said: “We are very excited about this award. The Japanese groups have developed some cutting-edge experimental technologies and we are very much looking forward to working with them to the benefit of all our groups. The award creates an opportunity to make significant progress in our understanding of how these organisms survive, colonise hosts and cause disease.”
The Japan Partnering Awards are run jointly with the Japan Science and Technology Agency (JST) to support scientists in the field of systems biology. Professor Douglas Kell, Chief Executive of the BBSRC, said: “Modern bioscience demands international collaboration. By working together across international borders we can generate faster progress and higher quality science than we can alone. This scheme, and the close relationship between BBSRC and the JST, allows us to foster and build links between UK and Japanese researchers.” This year’s awards have been made to four UK research groups — at the Universities of Oxford, Cambridge, Imperial and Nottingham — and their Japanese counterparts. The title of the Nottingham project is ‘Dynamic mathematical modelling of diversification of transcriptional regulatory networks underlying the genetic variation of E. coli species’.
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