Femtosecond crystallography of membrane proteins in the lipidic cubic phase

Wei Liu, Daniel Wacker, Chong Wang, Enrique Abola, Vadim Cherezov

Research output: Contribution to journalReview articlepeer-review

44 Scopus citations


Despite recent technological advances in heterologous expression, stabilization and crystallization of membrane proteins (MPs), their structural studies remain difficult and require new transformative approaches. During the past two years, crystallization in lipidic cubic phase (LCP) has started gaining a widespread acceptance, owing to the spectacular success in highresolution structure determination of G protein-coupled receptors (GPCRs) and to the introduction of commercial instrumentation, tools and protocols. The recent appearance of X-ray free-electron lasers (XFELs) has enabled structure determination from substantially smaller crystals than previously possible with minimal effects of radiation damage, offering new exciting opportunities in structural biology. The unique properties of LCP material have been exploited to develop special protocols and devices that have established a new method of serial femtosecond crystallography of MPs in LCP (LCP-SFX). In this method, microcrystals are generated in LCP and streamed continuously inside the same media across the intersection with a pulsed XFEL beam at a flow rate that can be adjusted to minimize sample consumption. Pioneering studies that yielded the first room temperature GPCR structures, using a few hundred micrograms of purified protein, validate the LCP-SFX approach and make it attractive for structure determination of difficult-to-crystallize MPs and their complexes with interacting partners. Together with the potential of femtosecond data acquisition to interrogate unstable intermediate functional states of MPs, LCP-SFX holds promise to advance our understanding of this biomedically important class of proteins.

Original languageEnglish
Article number20130314
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Issue number1647
StatePublished - 17 Jul 2014
Externally publishedYes


  • G protein-coupled receptor
  • Lipidic cubic phase
  • Membrane proteins
  • Serial femtosecond crystallography
  • X-ray free-electron laser


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