4WIO

Crystal structure of the C89A GMP synthetase inactive mutant from Plasmodium falciparum in complex with glutamine

Summary for 4WIO

• Entry DOI: 10.2210/pdb4wio/pdb
• Related: 4WIM 4WIN
• Descriptor: GMP synthetase, GLUTAMINE (3 entities in total)
• Functional Keywords: gmp synthetase, purine salvage pathway, ligase
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 1
• Total formula weight: 65458.51

Authors

Ballut, L.,Violot, S.,Haser, R.,Aghajari, N. (deposition date: 2014-09-26, release date: 2015-12-02, Last modification date: 2024-10-23)

Primary citation

Ballut, L.,Violot, S.,Shivakumaraswamy, S.,Thota, L.P.,Sathya, M.,Kunala, J.,Dijkstra, B.W.,Terreux, R.,Haser, R.,Balaram, H.,Aghajari, N.
Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation.
Nat Commun, 6:8930-8930, 2015

PubMed Abstract: GMP synthetase (GMPS), a key enzyme in the purine biosynthetic pathway performs catalysis through a coordinated process across two catalytic pockets for which the mechanism remains unclear. Crystal structures of Plasmodium falciparum GMPS in conjunction with mutational and enzyme kinetic studies reported here provide evidence that an 85° rotation of the GATase domain is required for ammonia channelling and thus for the catalytic activity of this two-domain enzyme. We suggest that conformational changes in helix 371-375 holding catalytic residues and in loop 376-401 along the rotation trajectory trigger the different steps of catalysis, and establish the central role of Glu374 in allostery and inter-domain crosstalk. These studies reveal the mechanism of domain rotation and inter-domain communication, providing a molecular framework for the function of all single polypeptide GMPSs and form a solid basis for rational drug design targeting this therapeutically important enzyme.

PubMed: 26592566
DOI: 10.1038/ncomms9930

Experimental method

X-RAY DIFFRACTION (3.15 Å)