Conserved water mediated recognition and the dynamics of active site Cys 331 and Tyr 411 in hydrated structure of human IMPDH-II.
Inosine monophosphate dehydrogenase (IMPDH) of human is involved in GMP biosynthesis pathway, increased level of IMPDH-II (an isoform of enzyme) activity have found in leukemic and sarcoma cells. Modeling and extensive molecular dynamics simulation (15 ns) studies of IMPDH-II (1B3O PDB structure) have indicated the intricate involvement of four conserved water molecules (W 1, W 2, W 3, and W 4) in the conformational transition or the mobilities of "flap" (residues 400-450) and "loop" (residues 325-342) regions in enzyme. The stabilization of active site residues Asn 303, Gly 324, Ser 329, Cys 331, Asp 364, and Tyr 411 through variable H-bonding coordination from the conserved water molecular center seems interesting in the uninhibited hydrated form of human IMPDH-II structures. This conformational transition or the flexibility of mobile regions, water molecular recognition to active site residues Cys 331 and Tyr 411, and the presence of a hydrophilic cavity approximately 540 Å(3) (enclaved by the loop and flap region) near the C-terminal surface of this enzyme may explore a rational hope toward the water mimic inhibitor or anticancer agent design for human.
Department of Chemistry, National Institute of Technology-Durgapur, West Bengal, Durgapur 713209, India.
Hridoy R
HR
Bairagya
Bishnu P
BP
Mukhopadhyay
Asim K
AK
Bera
D020134:Catalytic Domain / Q000502:physiology*; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011188:Potassium / Q000737:chemistry; D017434:Protein Structure, Tertiary; D014443:Tyrosine / Q000378:metabolism*; D014867:Water / Q000737:chemistry / Q000378:metabolism*
D014867:Water; D014443:Tyrosine; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D003545:Cysteine; D011188:Potassium