Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Metabolically-resistant synthetic bioisostere overlaid on natural 5-InsP7  (left) and its co-crystal structure (right)
Metabolically-resistant synthetic bioisostere overlaid on natural 5-InsP7 (left) and its co-crystal structure (right)

Structural snapshots of protein/ligand complexes are crucial to gain insight into enzymatic reaction mechanisms. Diphospho-myo-inositol polyphosphates such as 5-InsP7 regulate immunity and phosphate homeostasis and are phosphatase substrates.

Data from a tripartite collaboration, between the Potter group within Oxford Pharmacology, the NIH and Freiburg University, “A structural exposé of noncanonical molecular reactivity within the protein tyrosine phosphatase WPD loop” just published in Nature Communications include the first multiple substrate/enzyme crystal complexes from a variety of pre-reactant-, reactant-, intermediate- and product-bound states for a Cys-based Arabidopsis thaliana protein tyrosine phosphate-phosphatase lacking a functional canonical catalytic acid.

These provide the first data-driven mechanism for a reaction cycle that does not utilize any amino-acid residue as a general acid, showing how the enzyme is optimized for regiospecific and rapid hydrolysis of the β-phosphate of its pyrophosphate substrate and how the latter can drive its own hydrolysis.

The work used a metabolically-resistant synthetic 5-InsP7 bioisostere (pink ligand), designed in the Potter group that replaces the scissile 5-β-phosphate of 5-InsP7 (grey) with a phosphonodifluoromethyl group. The co-crystallized ligand orientates like 5-InsP7 but with a gain-of-function interaction between one fluorine atom and a guanidinium group. Very notably the work also identifies crystallographically a highly elusive and reactive metaphosphate-like intermediate in the reaction cycle.

Read the paper:

Similar stories

Consequences of Tau pathology on hippocampal pyramidal neurons and network activity in ageing mice

Pathological hyperphosphorylated forms of the microtubule-associated binding protein Tau (pTau) are commonly found in people with neurodegenerative diseases, including Alzheimer’s disease, Corticobasal degeneration, and Progressive supranuclear palsy.

Welcome to the 2022/23 academic year in Pharmacology!

At the start of this year, we have welcomed 23 new MSc in Pharmacology students, 13 new MSc(Res) and DPhil students and around a dozen additional project and visiting students from other Departments and other Universities. Some of these new starters joined existing staff, students and visitors in the Department for the first of a series of group photographs, to be taken every 6 months for our archives.

New Platt group paper explores links between Mycobacteria tuberculosis and Niemann-Pick Type C disease

Congratulations to Yuzhe Weng, a DPhil student in the Platt lab, who is first author on new paper published by the group in Nature Communications. Mycobacteria tuberculosis (Mtb), the causative agent of tuberculosis (TB), has the ability to invade, persist and replicate within host cells, which is key to its success as a pathogen. However, the mechanisms that underlie this strategy remain poorly defined.


We were sad to learn that our dear colleague Rebecca has died just a few days before what would have been her 63rd birthday.

New high-resolution imaging provides clue to SARS-CoV-2 leap to humans

A new paper, published this week in the journal Science, highlights cutting-edge imaging techniques used by the group of Professor Ben Davis to investigate the binding of SARS-CoV-2 to human cells.

Dr Mehmood Khan joins Pharmacology as a Visiting Fellow

We are delighted to announce the appointment of Dr Mehmood Khan as a Visiting Fellow in the Department