Protein

Good Things Come in Pairs: ��TV research shows enzymatic partners drive chemical reactions

ullahnor — Fri, 24 Feb 2017 17:03:56 +0000

Good Things Come in Pairs: ��TV research shows enzymatic partners drive chemical reactions

ullahnor Fri, 02/24/2017 - 12:03

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Professor Scott Prosser: “The research advances fundamental concepts regarding the role of enzyme dynamics in catalysis” (photo by Stephen Uhraney)

Nicolle Wahl

Author legacy

Nicolle Wahl

Topic

Breaking Research

Enzymes

Protein

��TV Mississauga

Biochemistry

New research from ��TV suggests that when it comes to chemistry, good things come in pairs.

Nature tends to package many enzymes as pairs or dimers and in many cases the dimeric enzymes exhibit cooperatively, that is they do not bind more than one substrate molecule at the same time.

Using X-ray crystallography and nuclear magnetic resonance, the team – led by co-authors ��TV professor Emil Pai and ��TV Mississauga professor Scott Prosser – captured high-resolution snapshots of the paired enzymes during various stages of catalysis.

“The research advances fundamental concepts regarding the role of enzyme dynamics in catalysis,” says Prosser. “By understanding how binding events regulate enzyme flexibility, we can better design drugs to affect changes on properties of target molecules in fighting disease.”

The findings highlight how paired or “dimeric” enzymes use their empty “seat” to drive a chemical reaction on their occupied half, meaning that after binding the first substrate in the dimer, binding and turnover of the second substrate becomes even faster.

The findings appear in a recent issue of the journal Science.

Enzymes, of which the vast majority are proteins, speed up chemical reactions in living organisms, without themselves being altered in the process.

Prosser and his colleagues at ��TV Mississauga recently uncovered another reason for this pairing, in their study of a bacterial enzyme, fluoroacetate dehalogenase. Namely, the empty seat of the dimer becomes dynamic upon binding to the substrate and helps drive forward the reaction. The role of this paired enzyme is to pry away a fluorine atom from an otherwise potent and lethal pesticide, fluoroacetate. This is no small feat – the carbon-fluorine bond is one of the strongest chemical bonds in nature.

As an aside, some plants are able to make this poison to protect themselves from grazing herbivores, who don’t have this enzyme and therefore – like humans – could be killed by this poison.

The empty half of the pair appears to still do a fair share of the work in accomplishing this reaction. As the poison binds to the dimer, the empty half sheds water molecules and become more dynamic at the same time, making the reaction more spontaneous. If the enzyme were to suddenly jiggle and lose water molecules in the bound half of the dimer this might spell disaster for the actual bond breaking chemical step – so the empty half of the dimer does the dirty work. The enzyme also prevents binding of a second molecule while it is focused on catalysis of the first molecule.

The team also found that water molecules aren’t just used by the enzyme as “ballast” to drive the reaction. Very subtle networks of these water molecules, appearing as constellations, distinguish the enzyme at each step along the reaction pathway.

As crystallographic resolution improves, scientists may find that these bound water networks are more involved in protein function than previously imagined.

Plastic makes perfect? ��TV researchers discover plastic helps them stabilize protein molecules to generate 3D structures

ullahnor — Tue, 07 Feb 2017 18:00:00 +0000

Plastic makes perfect? ��TV researchers discover plastic helps them stabilize protein molecules to generate 3D structures

ullahnor Tue, 02/07/2017 - 13:00

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��TV researchers Bryan T. Eger (left), Jana Broecker (middle) and Oliver P. Ernst (right) have discovered a way to stabilize proteins to make them available for 3D structure determination (photo by Sebastian Fiedler)

Heidi Singer

Author legacy

Heidi Singer

Topic

University of Toronto scientists have discovered a better way to extract proteins from the membranes that encase them, making it easier to study how cells communicate with each other to create human health and disease.

In a study published today on the cover of the journal Structure, Jana Broecker, a postdoctoral fellow in the lab of Biochemistry Professor Oliver P. Ernst, along with colleagues has discovered that a type of plastic or polymer – originally developed by the auto industry – can be used to better stabilize crucial proteins, thereby making them available for 3D structure determination.

The ability to determine the 3D atomic structure of protein molecules is critical in understanding how they work and how they will respond to drug therapies.

Along with Broecker's research which will help stabilize proteins, ��TV researchers led by ��TV Scarborough PhD student Ali Punjani earlier this week released a study showing that they've developed a new set of machine learning algorithms to generate 3D structures of tiny protein molecules, thus revolutionizing the development of drug therapies for a range of diseases.

New algorithms by ��TV researchers may revolutionize drug discoveries

ullahnor — Mon, 06 Feb 2017 16:14:36 +0000

New algorithms by ��TV researchers may revolutionize drug discoveries

ullahnor Mon, 02/06/2017 - 11:14

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��TV PhD student Ali Punjani says the ability to determine the 3D structures of protein is critical in understanding how they work and how they will respond to drug therapies (photo by Ken Jones)

Don Campbell

Author legacy

Don Campbell

Topic

Artificial Intelligence

A new set of machine learning algorithms developed by ��TV researchers that can generate 3D structures of tiny protein molecules may revolutionize the development of drug therapies for a range of diseases from Alzheimer’s to cancer.

“Designing successful drugs is like solving a puzzle,” says ��TV PhD student Ali Punjani, who helped develop the algorithms. “Without knowing the three-dimensional shape of a protein, it would be like trying to solve that puzzle with a blindfold on.”

The ability to determine the 3D atomic structure of protein molecules is critical in understanding how they work and how they will respond to drug therapies, notes Punjani.

Drugs work by binding to a specific protein molecule and changing its 3D shape, altering the way it works once inside the body. The ideal drug is designed in a shape that will only bind to a specific protein or proteins involved in a disease while eliminating side effects that occur when drugs bind to other proteins in the body.

At the same time, researcher Jana Broecker and colleagues in the Ernst lab in ��TV’s department of biochemistry have discovered a new way to obtain membrane-protein structures. Their research, to be published tomorrow on the cover of the journal Structure, should drastically speed up the discovery of new protein structures – thus also contributing to the development of new and better drugs.

In Punjani's research, the new set of algorithms reconstructs 3D structures of protein molecules using microscopic images. Since proteins are tiny – even smaller than a wavelength of light – they can’t be seen directly without using sophisticated techniques like electron cryomicroscopy (cryo-EM). This new method is revolutionizing the way scientists can discover 3D protein structures, allowing the study of many proteins that simply could not be studied in the past.

Cryo-EM is unique because it uses high-power microscopes to take tens of thousands of low-resolution images of a frozen protein sample from different positions. The computational problem is to then piece together the correct high-resolution 3D structure from the low-resolution 2D images.

“Our approach solves some of the major problems in terms of speed and number of structures you can determine,” says Professor David Fleet, chair of the computer and mathematical sciences department at ��TV Scarborough and Punjani’s PhD supervisor.

The algorithms, which were co-developed by Fleet’s former post-doctoral researcher Marcus Brubaker, now an assistant professor at York University, could significantly aid in the development of new drugs because they provide a faster, more efficient means at arriving at the correct protein structure.

“Existing techniques take several days or even weeks to generate a 3D structure on a cluster of computers,” says Brubaker. “Our approach can make it possible in minutes on a single computer.”

Punjani adds that existing techniques often generate incorrect structures unless the user provides an accurate guess of the molecule being studied. What’s novel about this approach is that it eliminates the need for prior knowledge about the protein molecule being studied.

“We hope this will allow discoveries to happen at a ground-breaking pace in structural biology,” says Punjani. “The ultimate goal is that it will directly lead to new drug candidates for diseases, and a much deeper understanding of how life works at the atomic level.”

The research, which included a collaboration with ��TV Professor John Rubinstein, a Canada Research Chair in Electron Cryomicroscopy, received funding from the Natural Sciences and Engineering Research Council of Canada (NSERC). It’s also been published in the current edition of the journal Nature Methods.

Meanwhile, the team’s startup, Structura Biotechnology Inc., has developed the algorithms into a new cryo-EM platform called cryoSPARC that is already being used in labs across North America.

The startup has received funding and support from ��TV’s Innovations and Partnership’s Office (IPO) through the Connaught Innovation Award, ��TV’s Early Stage Technologies (UTEST) program, the Ontario Centres of Excellence (OCE) and FedDev Ontario’s Investing in Commercialization Partnerships program with York University.

Good ribbance: ��TV researcher finds dino rib bones reveal remnants of 195-million-year-old protein

ullahnor — Wed, 01 Feb 2017 15:02:00 +0000

Good ribbance: ��TV researcher finds dino rib bones reveal remnants of 195-million-year-old protein

ullahnor Wed, 02/01/2017 - 10:02

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Skeleton of the 195-million-year-old dinosaur “Lufengosaurus” preserved as found in the ground in Yunnan Province, China. (photo courtesy of Robert Reisz)

Nicolle Wahl

Author legacy

Nicolle Wahl

Topic

Is fossilized rock all that remains when a dinosaur decomposes?

New research from scientists at the University of Toronto and researchers in China and Taiwan provides the first evidence that proteins have been preserved within the 195-million-year-old rib of the sauropodomorph dinosaur Lufengosaurus.

The study appears in the Jan. 31 issue of the journal Nature Communications and the news is already making headlines around the world.

Read The Washington Post story

“These dinosaur proteins are more than 100 million years older than anything previously discovered,” says Professor Robert Reisz, a specialist in vertebrate paleontology in the department of biology at ��TV Mississauga. “These proteins are the building blocks of animal soft tissues, and it’s exciting to understand how they have been preserved.”

Close up of a cross section of the “Lufengosaurus” rib, showing how the bone was organized around vascular canals that contained blood vessels in the living dinosaur, and ran along the length of the rib (photo courtesy of Robert Reisz)

The Canada-Taiwan research team, led by Reisz, used the synchrotron at the Taiwanese National Synchrotron Radiation Research Centre to find the substance in place, known as collagen type I, preserved within the tiny vascular canals of the rib where blood vessels and blood would be in the living dinosaur.

Protein

Good Things Come in Pairs: ��TV research shows enzymatic partners drive chemical reactions

Plastic makes perfect? ��TV researchers discover plastic helps them stabilize protein molecules to generate 3D structures

Read more about Punjani's research

New algorithms by ��TV researchers may revolutionize drug discoveries

Good ribbance: ��TV researcher finds dino rib bones reveal remnants of 195-million-year-old protein

Read The Washington Post story

Read more at the Globe and Mail

Read the Agence-France Presse story

Read more about the discovery at BBC News

Protein

Good Things Come in Pairs: ����TV research shows enzymatic partners drive chemical reactions

Plastic makes perfect? ����TV researchers discover plastic helps them stabilize protein molecules to generate 3D structures

Read more about Punjani's research

New algorithms by ����TV researchers may revolutionize drug discoveries

Good ribbance: ����TV researcher finds dino rib bones reveal remnants of 195-million-year-old protein

Read The Washington Post story

Read more at the Globe and Mail

Read the Agence-France Presse story

Read more about the discovery at BBC News

Good Things Come in Pairs: ��TV research shows enzymatic partners drive chemical reactions

Plastic makes perfect? ��TV researchers discover plastic helps them stabilize protein molecules to generate 3D structures

New algorithms by ��TV researchers may revolutionize drug discoveries

Good ribbance: ��TV researcher finds dino rib bones reveal remnants of 195-million-year-old protein