scholarly journals Temperature artifacts in protein structures bias ligand-binding predictions

2021 ◽  
Author(s):  
Shanshan YC Bradford ◽  
Lea El Khoury ◽  
Yunhui Ge ◽  
Meghan Osato ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Computational Methods ◽  
Protein Function ◽  
Gold Standard ◽  
Protein Structures ◽  
X Ray ◽  
Conformational Ensembles ◽  
X Ray Crystallography ◽  
Methods Development ◽  
Ligand Discovery

X-ray crystallography is the gold standard to resolve conformational ensembles that are significant for protein function, ligand discovery, and computational methods development. However, relevant conformational states may be missed at...

scholarly journals Role of Computational Methods in Going beyond X-ray Crystallography to Explore Protein Structure and Dynamics

2018 ◽  
Vol 19 (11) ◽  
pp. 3401 ◽  
Author(s):  
Ashutosh Srivastava ◽  
Tetsuro Nagai ◽  
Arpita Srivastava ◽  
Osamu Miyashita ◽  
Florence Tama
Keyword(s):  
Protein Dynamics ◽  
Computational Methods ◽  
Protein Structures ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
X Ray ◽  
X Ray Crystallography ◽  
Insight Into

Protein structural biology came a long way since the determination of the first three-dimensional structure of myoglobin about six decades ago. Across this period, X-ray crystallography was the most important experimental method for gaining atomic-resolution insight into protein structures. However, as the role of dynamics gained importance in the function of proteins, the limitations of X-ray crystallography in not being able to capture dynamics came to the forefront. Computational methods proved to be immensely successful in understanding protein dynamics in solution, and they continue to improve in terms of both the scale and the types of systems that can be studied. In this review, we briefly discuss the limitations of X-ray crystallography in studying protein dynamics, and then provide an overview of different computational methods that are instrumental in understanding the dynamics of proteins and biomacromolecular complexes.

scholarly journals Principles and characteristics of biological assemblies in experimentally determined protein structures

2019 ◽  
Author(s):  
Qifang Xu ◽  
Roland L. Dunbrack
Keyword(s):  
Physical Properties ◽  
Computational Methods ◽  
Structural Information ◽  
Protein Structures ◽  
Sequence Conservation ◽  
Homologous Proteins ◽  
X Ray ◽  
Biologically Relevant ◽  
X Ray Crystallography

AbstractMore than half of all structures in the PDB are assemblies of two or more proteins, including both homooligomers and heterooligomers. Structural information on these assemblies comes from X-ray crystallography, NMR, and cryo-EM spectroscopy. The correct assembly in an X-ray structure is often ambiguous, and computational methods have been developed to identify the most likely biologically relevant assembly based on physical properties of assemblies and sequence conservation in interfaces. Taking advantage of the large number of structures now available, some of the most recent methods have relied on similarity of interfaces and assemblies across structures of homologous proteins.

scholarly journals A Robust Method for Collecting X-ray Diffraction Data from Protein Crystals across Physiological Temperatures

2020 ◽  
Author(s):  
Tzanko Doukov ◽  
Daniel Herschlag ◽  
Filip Yabukarski
Keyword(s):  
Diffraction Data ◽  
Protein Function ◽  
Three Dimensional ◽  
Proteinase K ◽  
Protein Crystals ◽  
X Ray Diffraction ◽  
X Ray ◽  
Conformational Ensembles ◽  
X Ray Crystallography ◽  
Lysozyme Crystals

AbstractTraditional X-ray diffraction data collected at cryo-temperatures have delivered invaluable insights into the three-dimensional structures of proteins, providing the backbone of structure-function studies. While cryo-cooling mitigates radiation damage, cryo-temperatures can alter protein conformational ensembles and solvent structure. Further, conformational ensembles underlie protein function and energetics, and recent advances in room-temperature X-ray crystallography have delivered conformational heterogeneity information that is directly related to biological function. The next challenge is to develop a robust and broadly applicable method to collect single-crystal X-ray diffraction data at and above room temperatures and was addressed herein. This approach provides complete diffraction datasets with total collection times as short as ~5 sec from single protein crystals, dramatically increasing the amount of data that can be collected within allocated synchrotron beam time. Its applicability was demonstrated by collecting 1.09-1.54 Å resolution data over a temperature range of 293–363 K for proteinase K, thaumatin, and lysozyme crystals. Our analyses indicate that the diffraction data is of high-quality and do not suffer from excessive dehydration or damage.

scholarly journals Beyond History: The List of The Most Well Studied Human Protein Structures

2020 ◽  
Author(s):  
Zhenlu Li ◽  
Matthias Buck
Keyword(s):  
Protein Structures ◽  
Protein Sequences ◽  
Human Protein ◽  
Current Status ◽  
Protein Database ◽  
X Ray ◽  
X Ray Crystallography ◽  
Protein Biophysics ◽  
The Relationship ◽  
Past Trend

Of 20,000 or so canonical human protein sequences, as of July 2020, 6,747 proteins have had their full or partial medium to high-resolution structures determined by x-ray crystallography or other methods. Which of these proteins dominate the protein database (the PDB) and why? In this paper, we list the 272 top protein structures based on the number of their PDB depositions. This set of proteins accounts for more than 40% of all available human PDB entries and represent past trend and current status for protein science. We briefly discuss the relationship which some of the prominent protein structures have with protein biophysics research and mention their relevance to human diseases. The information may inspire researchers who are new to protein science, but it also provides a year 2020 snap-shot for the state of protein science.

scholarly journals Probing G-quadruplex topologies and recognition concurrently in real time and 3D using a dual-app nucleoside probe

2019 ◽  
Vol 47 (12) ◽  
pp. 6059-6072 ◽  
Author(s):  
Ashok Nuthanakanti ◽  
Ishtiyaq Ahmed ◽  
Saddam Y Khatik ◽  
Kayarat Saikrishnan ◽  
Seergazhi G Srivatsan
Keyword(s):  
Nucleic Acid ◽  
Ligand Binding ◽  
Real Time ◽  
Telomeric Dna ◽  
X Ray ◽  
X Ray Crystallography ◽  
New Class ◽  
Loop Region ◽  
Dna Repeat ◽  
G Quadruplex

Abstract Comprehensive understanding of structure and recognition properties of regulatory nucleic acid elements in real time and atomic level is highly important to devise efficient therapeutic strategies. Here, we report the establishment of an innovative biophysical platform using a dual-app nucleoside analog, which serves as a common probe to detect and correlate different GQ structures and ligand binding under equilibrium conditions and in 3D by fluorescence and X-ray crystallography techniques. The probe (SedU) is composed of a microenvironment-sensitive fluorophore and an excellent anomalous X-ray scatterer (Se), which is assembled by attaching a selenophene ring at 5-position of 2′-deoxyuridine. SedU incorporated into the loop region of human telomeric DNA repeat fluorescently distinguished subtle differences in GQ topologies and enabled quantify ligand binding to different topologies. Importantly, anomalous X-ray dispersion signal from Se could be used to determine the structure of GQs. As the probe is minimally perturbing, a direct comparison of fluorescence data and crystal structures provided structural insights on how the probe senses different GQ conformations without affecting the native fold. Taken together, our dual-app probe represents a new class of tool that opens up new experimental strategies to concurrently investigate nucleic acid structure and recognition in real time and 3D.

scholarly journals Structure and function of cement proteins in human adenovirus

2014 ◽  
Vol 70 (a1) ◽  
pp. C1603-C1603
Author(s):  
Vijay Reddy ◽  
Glen Nemerow
Keyword(s):  
Protein Structures ◽  
Human Adenovirus ◽  
Icosahedral Symmetry ◽  
Virion Assembly ◽  
X Ray ◽  
X Ray Crystallography ◽  
Capsid Shell ◽  
Multiple Copies ◽  
And Function ◽  
Cement Protein

Human adenoviruses (HAdVs) are large (~150nm in diameter, 150MDa) nonenveloped double-stranded DNA (dsDNA) viruses that cause respiratory, ocular, and enteric diseases. The capsid shell of adenovirus (Ad) comprises multiple copies of three major capsid proteins (MCP: hexon, penton base and fiber) and four minor/cement proteins (IIIa, VI, VIII and IX) that are organized with pseudo T=25 icosahedral symmetry. In addition, six other proteins (V, VII, μ, IVa2, terminal protein and protease) are encapsidated along with the 36Kb dsDNA genome inside the capsid. The crystal structures of all three MCPs are known and so is their organization in the capsid from prior X-ray crystallography and cryoEM analyses. However structures and locations of various cement proteins are of considerable debate. We have determined and refined the structure of an entire human adenovirus employing X-ray crystallpgraphic methods at 3.8Å resolution. Adenovirus cement proteins play crucial roles in virion assembly, disassembly, cell entry and infection. Based on the refined crystal structure of adenovirus, we have determined the structure of the cement protein VI, a key membrane-lytic molecule and its associations with proteins V and VIII, which together glue peripentonal hexons beneath vertex region and connect them to rest of the capsid. Following virion maturation, the cleaved N-terminal pro-peptide of VI is observed deep in the peripentonal hexon cavity, detached from the membrane-lytic domain. Furthermore, we have significantly revised the recent cryoEM models for proteins IIIa and IX and both are located on the capsid exterior. Together, the cement proteins exclusively stabilize the hexon shell, thus rendering penton vertices the weakest links of the adenovirus capsid. Adenovirus cement protein structures reveal the molecular basis of the maturation cleavage of VI that is needed for endosome rupture and delivery of the virion into cytoplasm.

scholarly journals Bence Jones KWR protein structures determined by X-ray crystallography

2007 ◽  
Vol 63 (7) ◽  
pp. 780-792 ◽  
Author(s):  
Debora L. Makino ◽  
Agnes H. Henschen-Edman ◽  
Steven B. Larson ◽  
Alexander McPherson
Keyword(s):  
Protein Structures ◽  
X Ray ◽  
X Ray Crystallography

Picosecond time-resolved X-ray crystallography: probing protein function in real time

2004 ◽  
Vol 147 (3) ◽  
pp. 235-246 ◽  
Author(s):  
Friedrich Schotte ◽  
Jayashree Soman ◽  
John S. Olson ◽  
Michael Wulff ◽  
Philip A. Anfinrud
Keyword(s):  
Real Time ◽  
Protein Function ◽  
Time Resolved ◽  
X Ray ◽  
X Ray Crystallography

scholarly journals xMDFF: molecular dynamics flexible fitting of low-resolution X-ray structures

2014 ◽  
Vol 70 (9) ◽  
pp. 2344-2355 ◽  
Author(s):  
Ryan McGreevy ◽  
Abhishek Singharoy ◽  
Qufei Li ◽  
Jingfen Zhang ◽  
Dong Xu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Protein Structures ◽  
Data Bank ◽  
Real Space ◽  
Low Resolution ◽  
X Ray ◽  
X Ray Crystallography ◽  
Atomic Structures ◽  
Electron Density Map

X-ray crystallography remains the most dominant method for solving atomic structures. However, for relatively large systems, the availability of only medium-to-low-resolution diffraction data often limits the determination of all-atom details. A new molecular dynamics flexible fitting (MDFF)-based approach, xMDFF, for determining structures from such low-resolution crystallographic data is reported. xMDFF employs a real-space refinement scheme that flexibly fits atomic models into an iteratively updating electron-density map. It addresses significant large-scale deformations of the initial model to fit the low-resolution density, as tested with synthetic low-resolution maps of D-ribose-binding protein. xMDFF has been successfully applied to re-refine six low-resolution protein structures of varying sizes that had already been submitted to the Protein Data Bank. Finally,viasystematic refinement of a series of data from 3.6 to 7 Å resolution, xMDFF refinements together with electrophysiology experiments were used to validate the first all-atom structure of the voltage-sensing protein Ci-VSP.

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