Download MendeleyMechanism of displacement of a catalytically essential loop from the active site of mammalian fructose-1,6-bisphosphatase.
Gao, Y., Iancu, C.V., Mukind, S., Choe, J.Y., Honzatko, R.B.(2013) Biochemistry 52: 5206-5216
- PubMed: 23844654
- DOI: https://doi.org/10.1021/bi400532n
- Primary Citation of Related Structures:
2F3B, 2F3D, 4KXP - PubMed Abstract:
AMP triggers a 15° subunit-pair rotation in fructose-1,6-bisphosphatase (FBPase) from its active R state to its inactive T state. During this transition, a catalytically essential loop (residues 50-72) leaves its active (engaged) conformation. Here, the structures of Ile(10) → Asp FBPase and molecular dynamic simulations reveal factors responsible for loop displacement. The AMP/Mg(2+) and AMP/Zn(2+) complexes of Asp(10) FBPase are in intermediate quaternary conformations (completing 12° of the subunit-pair rotation), but the complex with Zn(2+) provides the first instance of an engaged loop in a near-T quaternary state. The 12° subunit-pair rotation generates close contacts involving the hinges (residues 50-57) and hairpin turns (residues 58-72) of the engaged loops. Additional subunit-pair rotation toward the T state would make such contacts unfavorable, presumably causing displacement of the loop. Targeted molecular dynamics simulations reveal no steric barriers to subunit-pair rotations of up to 14° followed by the displacement of the loop from the active site. Principal component analysis reveals high-amplitude motions that exacerbate steric clashes of engaged loops in the near-T state. The results of the simulations and crystal structures are in agreement: subunit-pair rotations just short of the canonical T state coupled with high-amplitude modes sterically displace the dynamic loop from the active site.
Organizational Affiliation:
Department of Biochemistry, Biophysics, and Molecular Biology, 4206 Molecular Biology Building, Iowa State University , Ames, Iowa 50011-3260, United States.
