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Protein X-Ray Free Electron Laser (XFEL) Crystallography: A Novel Technology for Membrane Protein Structure and Drug Design

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 23609

Special Issue Editors

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
Interests: structure-function of oncogenic proteins, GPCR and proteogylycans; structural biology; protein dynamics; structure-based drug design; protein biochemistry; X-ray free electron crystallography
Special Issues, Collections and Topics in MDPI journals
Complex Systems Division, Beijing Computational Science Research Center, 8 E Xibeiwang Rd, Haidian, Beijing 100193, China
Interests: X-ray free electron laser applications in biomolecular structure and dynamics study; molecular dynamics simulations; structural-based drug design and screening; bioinformatics

Special Issue Information

Dear Colleagues,

X-ray free electron lasers (XFELs) can be used to determine protein structures from tiny crystals sized from sub-micron to microns, expanding the research in structure biology to a new horizon. Successful applications of XFEL have been reported continuously, from the determination of large molecular complexes, to atomic resolution structures, to membrane protein structures from 2D or 3D crystals, and to fast conformational changes using pump-probe time-resolved crystallography. The serial crystallography method with XFEL is especially powerful in the determination of membrane proteins, which are often drug receptors and make it difficult to obtain high quality large crystals using conventional crystallography. In addition, time-resolved structure determination provides unprecedented information regarding the detailed molecular mechanism of protein functions. Thanks to these important applications, XFEL facilities are rapidly constructed to become new bases in structure biology research.

Prof. Dr. Weontae Lee
Prof. Haiguang Liu
Guest Editors

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Keywords

  • Serial femtosecond crystallography
  • X-ray free electron laser
  • Time-resolved structure determination
  • Membrane protein structure
  • Lipidic cubic phase
  • Drug discovery
  • G-protein coupled receptors

Published Papers (5 papers)

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Editorial

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5 pages, 852 KiB  
Editorial
The XFEL Protein Crystallography: Developments and Perspectives
by Haiguang Liu and Weontae Lee
Int. J. Mol. Sci. 2019, 20(14), 3421; https://doi.org/10.3390/ijms20143421 - 12 Jul 2019
Cited by 12 | Viewed by 4159
Abstract
In the past 10 years, the world has witnessed the revolutionary development of X-ray free electron lasers (XFELs) and their applications in many scientific disciplinaries [...] Full article
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Research

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15 pages, 5093 KiB  
Article
Non-Cryogenic Structure and Dynamics of HIV-1 Integrase Catalytic Core Domain by X-ray Free-Electron Lasers
by Jae-Hyun Park, Ji-Hye Yun, Yingchen Shi, Jeongmin Han, Xuanxuan Li, Zeyu Jin, Taehee Kim, Jaehyun Park, Sehan Park, Haiguang Liu and Weontae Lee
Int. J. Mol. Sci. 2019, 20(8), 1943; https://doi.org/10.3390/ijms20081943 - 20 Apr 2019
Cited by 6 | Viewed by 3367
Abstract
HIV-1 integrase (HIV-1 IN) is an enzyme produced by the HIV-1 virus that integrates genetic material of the virus into the DNA of infected human cells. HIV-1 IN acts as a key component of the Retroviral Pre-Integration Complex (PIC). Protein dynamics could play [...] Read more.
HIV-1 integrase (HIV-1 IN) is an enzyme produced by the HIV-1 virus that integrates genetic material of the virus into the DNA of infected human cells. HIV-1 IN acts as a key component of the Retroviral Pre-Integration Complex (PIC). Protein dynamics could play an important role during the catalysis of HIV-1 IN; however, this process has not yet been fully elucidated. X-ray free electron laser (XFEL) together with nuclear magnetic resonance (NMR) could provide information regarding the dynamics during this catalysis reaction. Here, we report the non-cryogenic crystal structure of HIV-1 IN catalytic core domain at 2.5 Å using microcrystals in XFELs. Compared to the cryogenic structure at 2.1 Å using conventional synchrotron crystallography, there was a good agreement between the two structures, except for a catalytic triad formed by Asp64, Asp116, and Glu152 (DDE) and the lens epithelium-derived growth factor binding sites. The helix III region of the 140–153 residues near the active site and the DDE triad show a higher dynamic profile in the non-cryogenic structure, which is comparable to dynamics data obtained from NMR spectroscopy in solution state. Full article
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14 pages, 2652 KiB  
Communication
Serial Femtosecond X-Ray Diffraction of HIV-1 Gag MA-IP6 Microcrystals at Ambient Temperature
by Halil I Ciftci, Raymond G Sierra, Chun Hong Yoon, Zhen Su, Hiroshi Tateishi, Ryoko Koga, Koiwai Kotaro, Fumiaki Yumoto, Toshiya Senda, Mengling Liang, Soichi Wakatsuki, Masami Otsuka, Mikako Fujita and Hasan DeMirci
Int. J. Mol. Sci. 2019, 20(7), 1675; https://doi.org/10.3390/ijms20071675 - 03 Apr 2019
Cited by 4 | Viewed by 3679
Abstract
The Human immunodeficiency virus-1 (HIV-1) matrix (MA) domain is involved in the highly regulated assembly process of the virus particles that occur at the host cell’s plasma membrane. High-resolution structures of the MA domain determined using cryo X-ray crystallography have provided initial insights [...] Read more.
The Human immunodeficiency virus-1 (HIV-1) matrix (MA) domain is involved in the highly regulated assembly process of the virus particles that occur at the host cell’s plasma membrane. High-resolution structures of the MA domain determined using cryo X-ray crystallography have provided initial insights into the possible steps in the viral assembly process. However, these structural studies have relied on large and frozen crystals in order to reduce radiation damage caused by the intense X-rays. Here, we report the first X-ray free-electron laser (XFEL) study of the HIV-1 MA domain’s interaction with inositol hexaphosphate (IP6), a phospholipid headgroup mimic. We also describe the purification, characterization and microcrystallization of two MA crystal forms obtained in the presence of IP6. In addition, we describe the capabilities of serial femtosecond X-ray crystallography (SFX) using an XFEL to elucidate the diffraction data of MA-IP6 complex microcrystals in liquid suspension at ambient temperature. Two different microcrystal forms of the MA-IP6 complex both diffracted to beyond 3.5 Å resolution, demonstrating the feasibility of using SFX to study the complexes of MA domain of HIV-1 Gag polyprotein with IP6 at near-physiological temperatures. Further optimization of the experimental and data analysis procedures will lead to better understanding of the MA domain of HIV-1 Gag and IP6 interaction at high resolution and will provide basis for optimization of the lead compounds for efficient inhibition of the Gag protein recruitment to the plasma membrane prior to virion formation. Full article
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Review

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23 pages, 3798 KiB  
Review
Time-Resolved Macromolecular Crystallography at Pulsed X-ray Sources
by Marius Schmidt
Int. J. Mol. Sci. 2019, 20(6), 1401; https://doi.org/10.3390/ijms20061401 - 20 Mar 2019
Cited by 38 | Viewed by 6487
Abstract
The focus of structural biology is shifting from the determination of static structures to the investigation of dynamical aspects of macromolecular function. With time-resolved macromolecular crystallography (TRX), intermediates that form and decay during the macromolecular reaction can be investigated, as well as their [...] Read more.
The focus of structural biology is shifting from the determination of static structures to the investigation of dynamical aspects of macromolecular function. With time-resolved macromolecular crystallography (TRX), intermediates that form and decay during the macromolecular reaction can be investigated, as well as their reaction dynamics. Time-resolved crystallographic methods were initially developed at synchrotrons. However, about a decade ago, extremely brilliant, femtosecond-pulsed X-ray sources, the free electron lasers for hard X-rays, became available to a wider community. TRX is now possible with femtosecond temporal resolution. This review provides an overview of methodological aspects of TRX, and at the same time, aims to outline the frontiers of this method at modern pulsed X-ray sources. Full article
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18 pages, 2346 KiB  
Review
Sample Delivery Media for Serial Crystallography
by Ki Hyun Nam
Int. J. Mol. Sci. 2019, 20(5), 1094; https://doi.org/10.3390/ijms20051094 - 04 Mar 2019
Cited by 43 | Viewed by 4709
Abstract
X-ray crystallographic methods can be used to visualize macromolecules at high resolution. This provides an understanding of molecular mechanisms and an insight into drug development and rational engineering of enzymes used in the industry. Although conventional synchrotron-based X-ray crystallography remains a powerful tool [...] Read more.
X-ray crystallographic methods can be used to visualize macromolecules at high resolution. This provides an understanding of molecular mechanisms and an insight into drug development and rational engineering of enzymes used in the industry. Although conventional synchrotron-based X-ray crystallography remains a powerful tool for understanding molecular function, it has experimental limitations, including radiation damage, cryogenic temperature, and static structural information. Serial femtosecond crystallography (SFX) using X-ray free electron laser (XFEL) and serial millisecond crystallography (SMX) using synchrotron X-ray have recently gained attention as research methods for visualizing macromolecules at room temperature without causing or reducing radiation damage, respectively. These techniques provide more biologically relevant structures than traditional X-ray crystallography at cryogenic temperatures using a single crystal. Serial femtosecond crystallography techniques visualize the dynamics of macromolecules through time-resolved experiments. In serial crystallography (SX), one of the most important aspects is the delivery of crystal samples efficiently, reliably, and continuously to an X-ray interaction point. A viscous delivery medium, such as a carrier matrix, dramatically reduces sample consumption, contributing to the success of SX experiments. This review discusses the preparation and criteria for the selection and development of a sample delivery medium and its application for SX. Full article
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