Protein architecture findings may aid drug design
Researchers from Nanyang Technological University’s (NTU) School of Physical and Mathematical Sciences (SPMS) have taken a major step forward in the effort to understand and engineer protein structure, which could lead to potential benefits in the fields of drug design and nanomaterials.
Assistant Professor Brendan P. Orner and his team of researchers, including PhD and undergraduate students from SPMS’ Division of Chemistry & Biological Chemistry (CBC), have gained key insights into the architecture of a protein that controls iron levels in almost all organisms.
Their research on the protein ferritin has culminated in one of the first successful attempts to take apart a complex biological nanostructure and isolate the rules that govern its assembly – work that could lead to a fundamental understanding of the interactions that lead to brain deposits in many diseases associated with aging.
The research team’s study is published in this week’s issue of the Journal of Biological Chemistry. The article has been named a “Paper of the Week”, putting it in the top 1 percent of papers reviewed by the editorial board in terms of significance and overall importance.
“Engineering the structure of a protein is one of the ultimate dreams of structural biologists,” wrote one of the journal’s peer reviewers, “and approaching that dream is greatly enabled through studies aimed at finding out what governs the nanoarchitecture of the protein.”
Ferritin regulates the distribution of iron, which is necessary for a number of cellular functions, but iron also forms reactive ions that can be potentially damaging to DNA molecules and thus lead to cancer. Shaped like a spherical nanocage, ferritin is made up of 24 proteins and it safely stores the reactive iron in its hollow interior.
Opening the door to eventual drug design
“The rules that govern self-assembling nanosystems, like the ferritin model, are poorly understood,” said Asst Prof Orner. “Our findings have helped us to understand what controls this assembly. We have learned how to disrupt it and stabilise it in a specific system. Understanding the interactions involved in the assembly of this nanocage could open the door to eventual drug design that will disrupt the structure and function of defective proteins that cause or contribute to disease.”
Asst Prof Orner added that interactions between proteins, known as “protein-protein interactions”, are involved ubiquitously across biology and it is the “misfolding of proteins” that causes diseases associated with aging such as Alzheimer’s, Parkinson’s, and Huntington’s in addition to those similar to mad-cow disease.
“Protein-protein interactions form a huge new class of drug targets. Our research has added to the understanding of the fundamentals of protein-protein interactions, creating opportunities for better drug design,” said Asst Prof Orner on a possible application of the research findings. “Eventually key protein-protein interactions will be manipulated with therapies to treat diseases such as cancer,” he added.
Asst Prof Orner’s team included doctoral students Yu Zhang and Rongli Fan and undergraduate students Siti Raudah, Huihian Teo, Gwenda Teo, and Xioming Sun. The team is particularly interested in growing nanoparticles of precise dimensions inside ferritin shells. They have already developed a method of growing gold nanoparticles in them.
“Our investigation into the structure and energetics of the self-assembling nano-cage protein can act as a jumping off point for the eventual design of novel protein nanostructures,” said Yu Zhang, the paper’s first author. “These novel protein structures could be applied to the gold nanoparticle technology to produce nanoparticles with novel sizes and shapes.”
These nanoparticles can be used to perform drug screening of protein-protein interactions involved in, for example, virus infection and cancer, thus aiding drug design.
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