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

Emptage group successful with £1m MRC-AMED award

Congratulations to the group of Professor Nigel Emptage who have been awarded an MRC-AMED grant, worth £1m, in conjuction with the University of Tokyo and the RIKEN Center for Brain Science

Burton group wins image competition at Oxford BHF CRE Annual Symposium

This image of a blood clot composed of erythrocytes trapped by long fibrous chains of fibrin was judged the winner of the image competition at the BHF CRE 2022 Symposiium, held in December. In this image we can see false coloured erythrocytes (classic biconcave appearance around 5-10 µm in diameter) wrapped by fibrin network.

Understanding the brain at Didcot Girls School Science Club

A group of researchers and students led by Dr Tim Viney visited Didcot Girls School to run a ‘hands on’ event about the brain at the school’s Science Club.

Raised intracellular chloride levels underlie the effects of tiredness in cortex

The feeling of being tired is familiar to everyone. As we know from our own experience, an extended period of wakefulness results in a decline in our performance levels, and the desire to sleep becomes almost irresistible. When you then fall asleep, your sleep is deeper and more consolidated than usual. And yet after just one night of uninterrupted sleep, you can feel refreshed and “back to normal”!

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.