Membrane Protein Crystallography

Dear Colleagues,

The three-dimensional atomic structures of membrane proteins are indispensable for understanding their molecular mechanisms and provide the structural bases for rational protein engineering and inhibitor design. Although membrane proteins comprise approximately 30% of all proteins in living organisms, only 1.5% of proteins available in the Protein Data Bank (PDB) are membrane protein structures. Crystallography is a powerful technology for protein structure determination. Indeed, since 1985, the first high-resolution atomic structure of a photosynthetic reaction center from the bacterium Rhodopseudomonas virdis was determined using X-ray crystallography; many such structures have since been determined through this method. However, membrane protein structure determination through crystallography presents tremendous challenges due to the limitation of crystallization. Many innovative alternative crystallization strategies have thus been developed.

Recent advances in cryo-EM technology have thrust membrane protein structural biology into the spotlight. Many crystallization-resistant membrane proteins can be investigated by single-particle cryo-EM or cryo-EM tomography (especially large membrane protein complexes). Due to its advantages, single-particle cryo-EM has attracted many structural biologists, mainly crystallographers; however, the further development of membrane protein crystallography should not be neglected. We need a breakthrough in membrane protein crystallization equal to that of the current direct detector in the cryo-EM field. With this aim in mind, it is critical we summarize the past decades' successes and failures (from 1985 to 2022).

This Special Issue of Crystals will provide a forum for discussion on the current state of membrane protein crystallography by collecting contributions related to the structure and function of membrane proteins and related technology relating to subjects including, but not limited to, the following:

• Membrane protein expression and purification;
• Membrane protein reconstitution and characterization;
• Membrane protein engineering;
• Pre-crystallization screening for membrane proteins;
• Membrane protein stabilization in detergents, lipids, etc.;
• Membrane protein crystallization methods and strategies such as lipid cubic phase;
• Membrane protein crystallization chaperons (antibody, fusion protein);
• Phasing membrane proteins using ab initio methods and molecular replacement, including AlphaFold;
• Preparation and manipulation of microcrystals of membrane proteins;
• Synchrotron X-ray microdiffraction experiments optimized for membrane protein crystals;
• Application of X-ray free-electron lasers for studying membrane protein structure;
• Micro-ED experiments for membrane protein crystals;
• 2D electron crystallography;
• Technologies for the investigation of membrane protein structures in distinct conformational states;
• Exploring membrane protein structural dynamics using time-resolved crystallography;
• Small-molecule drug discovery and development targeting membrane proteins;
• Structural analysis of membrane protein complexes.

We welcome research on the structure determination of membrane proteins from all protein families using X-ray crystallography and its remaining challenges. This unique collection will be invaluable for membrane protein crystallographers and general membrane protein researchers in academic and industrial environments. Research articles, review articles, or communications articles from researchers who have made significant contributions in the crystal structure determination of a given membrane protein family are welcome.

Dr. Qun Liu
Dr. Dianfan Li
Dr. Youzhong Guo
Dr. Albert Guskov
Dr. Michael C. Wiener
Guest Editors

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