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Special Issue "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).

Special Issue Editors

Guest Editor
Prof. Dr. Weontae Lee Website E-Mail
Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, 134 Shinchon-Dong, Seodaemoon-Gu, Seoul, 120-749, 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
Guest Editor
Prof. Haiguang Liu Website E-Mail
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

Manuscript Submission Information

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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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Open AccessEditorial
The XFEL Protein Crystallography: Developments and Perspectives
Int. J. Mol. Sci. 2019, 20(14), 3421; https://doi.org/10.3390/ijms20143421 - 12 Jul 2019
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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Open AccessArticle
Non-Cryogenic Structure and Dynamics of HIV-1 Integrase Catalytic Core Domain by X-ray Free-Electron Lasers
Int. J. Mol. Sci. 2019, 20(8), 1943; https://doi.org/10.3390/ijms20081943 - 20 Apr 2019
Cited by 1
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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Open AccessCommunication
Serial Femtosecond X-Ray Diffraction of HIV-1 Gag MA-IP6 Microcrystals at Ambient Temperature
Int. J. Mol. Sci. 2019, 20(7), 1675; https://doi.org/10.3390/ijms20071675 - 03 Apr 2019
Cited by 1
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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Open AccessReview
Time-Resolved Macromolecular Crystallography at Pulsed X-ray Sources
Int. J. Mol. Sci. 2019, 20(6), 1401; https://doi.org/10.3390/ijms20061401 - 20 Mar 2019
Cited by 3
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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Open AccessReview
Sample Delivery Media for Serial Crystallography
Int. J. Mol. Sci. 2019, 20(5), 1094; https://doi.org/10.3390/ijms20051094 - 04 Mar 2019
Cited by 4
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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