Featured Research

from universities, journals, and other organizations

Structural Mechanism Of Cell Enzyme Revealed By UT Southwestern Researchers

Date:
July 22, 2002
Source:
University Of Texas Southwestern Medical Center At Dallas
Summary:
UT Southwestern Medical Center at Dallas researchers, using X-ray crystallography, have discovered how a particular cell enzyme finds its target and clearly carries out its role in the complicated process of cellular communication. The discovery could lead to the development of drugs that specifically target certain enzymes to prevent the onset of disease.

DALLAS – July 19, 2002 – UT Southwestern Medical Center at Dallas researchers, using X-ray crystallography, have discovered how a particular cell enzyme finds its target and clearly carries out its role in the complicated process of cellular communication.

The discovery could lead to the development of drugs that specifically target certain enzymes to prevent the onset of disease.

The research, led by Dr. Elizabeth Goldsmith, professor of biochemistry at UT Southwestern, is published in the June issue of Molecular Cell. It reveals how the mitogen-activating protein (MAP) kinase enzyme p38 maintains fidelity along its cell-signaling pathway.

Scientists previously believed that mammalian enzymes contained only one binding site (a place on a protein that recognizes another protein or molecule) for their substrates (substances acted upon and changed by the enzymes) - and that was the active site that acted to change the substrate. Now they recognize that some enzymes, for example, protein kinases, contain two binding sites: one is the active site and the second is a site that tethers the substrate to the enzyme until the time that the active site is ready to act on it. Goldsmith's work shows how this second binding site works.

"The enzyme p38 itself could be viewed as a switch in the cellular signaling process," said Dr. Melanie Cobb, professor of pharmacology and co-author of the study. "Its quest, once it's turned on, is to find the right target. It does that through the method described in this research. Multiple switches give the cell choices, and this shows how those choices are made."

The research was carried out primarily by Chung-I Chang, a student in molecular biophysics in the Southwestern Graduate School of Biomedical Sciences.

MAP kinases are a group of enzymes that mediate many cellular processes, including responses to hormones and drugs, to ultimately prompt certain changes in the body. This cellular signaling is necessary for every function.

"Signaling cascades are an important 'middle man' in the body's responses to the environment and modulate cell growth and differentiation," Goldsmith said. "MAP kinase cascades are drug targets for inflammation and cancer."

Since enzymes recognize certain targets in cells, drugs might be developed to specifically block interaction or recognition of individual targets by MAP kinases, Cobb said. These MAP kinases have numerous targets, and some can go wrong; for example, blocking interaction of p38 with selected targets might prevent inflammation.

X-ray crystallography allows researchers to "see" protein interactions at an amino acid level – a much higher resolution than with light microscopy – and data from this technique provides insight into which amino acids are important in protein binding. Knowing which specific amino acids recognize the MAP kinase p38 signaling pathway allows researchers to determine how the pathway maintains its fidelity and cascade establishment from other MAP kinase pathways.

"When you shine X-rays onto a crystallized protein, it produces a pattern of spots," said Goldsmith. "These spots have different intensities and positions, which tell the actual arrangement of the atomic structure within the molecule. The enzymes that precede and follow the MAP kinase p38 in a particular cascade both interact with it in the same location."

Some of the ideas suggested from the structure were confirmed by site-directed mutagenesis - the controlled alteration of selected regions of a molecule - conducted in the lab of Cobb, holder of the Jane and Bill Browning Jr. Chair in Medical Science. Goldsmith said when the activating enzyme binds to p38, it causes conformational changes in the activating site, making p38 more receptive to substrate binding.

"What was unexpected were the allosteric changes – protein conformation changes – far from the initial binding site," Goldsmith said. "This opens up areas to understand the kinetics of the entire system. The big question of these signal amplification cascades is how they achieve this amplification. What is the mechanism?"

Dr. Bing-e Xu, a pharmacology researcher working with Cobb, and Akella Radha, research scientist in biochemistry, also contributed to the study.

The research was supported by grants from the National Institutes of Health and the Welch Foundation.


Story Source:

The above story is based on materials provided by University Of Texas Southwestern Medical Center At Dallas. Note: Materials may be edited for content and length.


Cite This Page:

University Of Texas Southwestern Medical Center At Dallas. "Structural Mechanism Of Cell Enzyme Revealed By UT Southwestern Researchers." ScienceDaily. ScienceDaily, 22 July 2002. <www.sciencedaily.com/releases/2002/07/020722072800.htm>.
University Of Texas Southwestern Medical Center At Dallas. (2002, July 22). Structural Mechanism Of Cell Enzyme Revealed By UT Southwestern Researchers. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2002/07/020722072800.htm
University Of Texas Southwestern Medical Center At Dallas. "Structural Mechanism Of Cell Enzyme Revealed By UT Southwestern Researchers." ScienceDaily. www.sciencedaily.com/releases/2002/07/020722072800.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins