Nav: Home

Neutron crystallography aids in drug design

September 07, 2016

Neutron crystallography is an important complementary technique to X-ray crystallography since it provides details of the hydrogen atom and proton positions in biological molecules. Furthermore, as neutrons are a non-destructive probe, the resulting structures are free from radiation damage even at room temperature. Knowledge of H-bonding networks, water molecule orientations and protonation states, along with details of hydrophobic and electrostatic interactions, can prove vital towards a better understanding of many biological processes, such as enzyme mechanisms and can help guide structure-based drug design.

The first neutron crystallography study of a clinically used drug bound to its target was that of acetazolamide (AZM), a sulphonamide, which binds with high affinity to human carbonic anhydrase isoform II. Human carbonic anhydrases (hCA) are zinc metalloenzymes that catalyse the interconversion of CO2 and H2O to HCO3- and H+, an important reaction for many physiological processes including respiration, fluid secretion and pH regulation. As such hCA isoforms are prominent clinical targets for treating various diseases, such as glaucoma and epilepsy. hCA II is one of 12 catalytically active isoforms and, due to sequence conservation between them, substantial off-target binding to other isoforms occurs, reducing drug efficiency and causing side effects. Hence, there is a need to design effective hCA isoform-specific drugs. Over 400 X-ray crystal structures have been determined for hCA II, with around half of these in complex with inhibitors, yet despite the large amount of X-ray structural data available, key details regarding the H-atom positions of the protein and solvent and the charged state of the bound inhibitor were, until recently, missing for all but the hCA II/acetazolamide complex.

In the September issue of IUCrJ [Aggarwal et al. (2016), IUCrJ. 3, 319-325; doi:10.1107/S2052252516010514] McKenna and co-workers describe X-ray and neutron crystallographic studies of hCA II in complex with the inhibitor methoazolamide (MZM) providing missing details of the H-bonding and hydrophobic interactions in the complex, and identifying the charged state of MZM. They then compare the binding of AZM and MZM in the room-temperature neutron structures and discuss the observed differences in binding in terms of the enthalpic and entropic contributions to drug binding, suggesting that in the case of MZM, hydrophobic forces perhaps compensate for the loss of an extensive H-bonding network.

Over the past few years, a growing number of neutron structures have been deposited in the Protein Data Bank, including a number of other examples of enzyme-drug complexes. Although the overall number of neutron structures is still relatively small, there are growing numbers of examples for which neutron crystallography has provided the answers to questions that have remained elusive using other techniques.

International Union of Crystallography

Related Protein Articles:

Hi-res view of protein complex shows how it breaks up protein tangles
A new, high-resolution view of the structure of Hsp104 (heat shock protein 104), a natural yeast protein nanomachine with six subunits, may show news ways to dismantle harmful protein clumps in disease.
Breaking the protein-DNA bond
A new Northwestern University study finds that unbound proteins in a cell break up protein-DNA bonds as they compete for the single-binding site.
FASEB Science Research Conference: Protein Kinases and Protein Phosphorylation
This conference focuses on the biology of protein kinases and phosphorylation signaling.
Largest resource of human protein-protein interactions can help interpret genomic data
An international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression.
STAT2: Much more than an antiviral protein
A protein known for guarding against viral infections leads a double life, new research shows, and can interfere with cell growth and the defense against parasites.
A protein makes the difference
It is well-established knowledge that blood vessels foster the growth of tumors.
Nuclear protein causes neuroblastoma to become more aggressive
Aggressive forms of neuroblastoma contain a specific protein in their cells' nuclei that is not found in the nuclei of more benign forms of the cancer, and the discovery, made through research from the University of Rochester Medical Center, could lead to new forms of targeted therapy.
How a protein could become the next big sweetener
High-fructose corn syrup and sugar are on the outs with calorie-wary consumers.
High animal protein intake associated with higher, plant protein with lower mortality rate
The largest study to examine the effects of different sources of dietary protein found that a high intake of proteins from animal sources -- particularly processed and unprocessed red meats -- was associated with a higher mortality rate, while a high intake of protein from plant sources was associated with a lower risk of death.
Protein in, ammonia out
A recent study has compiled and analyzed data from 25 previous studies.

Related Protein Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...