6PS8

XFEL MT1R structure by ligand exchange from agomelatine to 2-phenylmelatonin.

Summary for 6PS8

• Entry DOI: 10.2210/pdb6ps8/pdb
• Descriptor: Fusion protein of Melatonin receptor type 1A and GlgA glycogen synthase, N-[2-(5-methoxy-2-phenyl-1H-indol-3-yl)ethyl]acetamide (2 entities in total)
• Functional Keywords: gpcr, complex-lcp method, sbdd, drug design, xfel, lcp-sfx, ligand exchange, agomelatine, 2-phenyl melatonin, membrane protein, mt1
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 56905.73

Authors

Ishchenko, A.,Stauch, B.,Han, G.W.,Batyuk, A.,Shiriaeva, A.,Li, C.,Zatsepin, N.A.,Weierstall, U.,Liu, W.,Nango, E.,Nakane, T.,Tanaka, R.,Tono, K.,Joti, Y.,Iwata, S.,Moraes, I.,Gati, C.,Cherezov, C. (deposition date: 2019-07-12, release date: 2019-11-13, Last modification date: 2023-10-11)

Primary citation

Ishchenko, A.,Stauch, B.,Han, G.W.,Batyuk, A.,Shiriaeva, A.,Li, C.,Zatsepin, N.,Weierstall, U.,Liu, W.,Nango, E.,Nakane, T.,Tanaka, R.,Tono, K.,Joti, Y.,Iwata, S.,Moraes, I.,Gati, C.,Cherezov, V.
Toward G protein-coupled receptor structure-based drug design using X-ray lasers.
Iucrj, 6:1106-1119, 2019

PubMed Abstract: Rational structure-based drug design (SBDD) relies on the availability of a large number of co-crystal structures to map the ligand-binding pocket of the target protein and use this information for lead-compound optimization via an iterative process. While SBDD has proven successful for many drug-discovery projects, its application to G protein-coupled receptors (GPCRs) has been limited owing to extreme difficulties with their crystallization. Here, a method is presented for the rapid determination of multiple co-crystal structures for a target GPCR in complex with various ligands, taking advantage of the serial femtosecond crystallography approach, which obviates the need for large crystals and requires only submilligram quantities of purified protein. The method was applied to the human β-adrenergic receptor, resulting in eight room-temperature co-crystal structures with six different ligands, including previously unreported structures with carvedilol and propranolol. The generality of the proposed method was tested with three other receptors. This approach has the potential to enable SBDD for GPCRs and other difficult-to-crystallize membrane proteins.

PubMed: 31709066
DOI: 10.1107/S2052252519013137

Experimental method

X-RAY DIFFRACTION (3.3 Å)