Structure of important malaria enzyme solved

02 May 2014

X-ray crystal structure of SUB1 from the malaria parasite, Plasmodium falciparum.

Image: X-ray crystal structure of SUB1 from the malaria parasite, Plasmodium falciparum.

Scientists have discovered the crystallographic structure of SUB1, a malaria enzyme that plays an important role in the transmission of the disease.

The structure reveals how SUB1 is regulated. It's hoped that the findings will help in the search for new antimalarial drugs that block SUB1.

The SUB1 enzyme is a protease - which means its job is to modify other proteins by cutting bonds between the amino acids from which they are built. SUB1 requires calcium to carry out its function.

Professor Mike Blackman of the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute) explained: "The malaria parasite invades a red blood cell, where it replicates. The resulting daughter cells - called merozoites - are then released in a process known as egress, destroying the host cell.

"Egress requires SUB1 to modify a set of proteins in the malaria parasite that play essential roles in invasion and egress. How SUB1 recognises these protein substrates, and how its activity is controlled, was previously unclear."

Mike Blackman's NIMR team used x-ray crystallography to solve the structure of SUB1 from Plasmodium falciparum, the most dangerous species of human malaria parasite.

This structure showed that SUB1 has three binding sites for calcium, explaining its calcium dependence. It also suggested that SUB1 is highly specific in how it recognises the proteins it is to modify - providing information essential for the design of SUB1 inhibitors that may have potential as antimalarial drugs.

An unexpected finding was the presence of an environmentally sensitive 'switch' that is thought to suppress the enzyme's activity during storage before egress - another possble target for new drugs.

Dr Chrislaine Withers-Martinez from the Blackman group said: "SUB1 is a key player in the pathway that leads to egress of invasive malaria merozoites. This new structural information enormously improves our understanding of how the enzyme is regulated and how to design inhibitors that can block the parasite life cycle and so control or prevent malaria."

Mike Blackman added: "Our finding that SUB1 has novel characteristics that set it apart from human proteases is really encouraging in our search for selective drug-like inhibitors.

"This is an excellent example of how x-ray crystallography can provide completely unexpected insights into the molecular mechanisms used by pathogens to infect and survive in their hosts."

The paper, The malaria parasite egress protease SUB1 is a calcium-dependent redox switch subtilisin, is published in Nature Communications.

  • Researchers at the Medical Research Council's National Institute for Medical Research have used x-ray crystallography to solve the structure of a key malaria parasite enzyme called SUB1. The work is hoped to help in the search for new drugs.
  • Malaria remains one of the most devastating diseases in the developing world. The most commonly used drugs are failing rapidly due to resistance, alternatives are expensive and there is no vaccine.
  • Previous work led by Professor Blackman found that as well as being involved in the blood stage of malaria, SUB1 is also crucial to the liver stage of infection.