STEREOSPECIFIC DIHALOALKANE BINDING IN A PH-SENSITIVE CAVITY IN CUBIC INSULIN CRYSTALS

被引:21
作者
GURSKY, O [1 ]
FONTANO, E [1 ]
BHYRAVBHATLA, B [1 ]
CASPAR, DLD [1 ]
机构
[1] BRANDEIS UNIV,ROSENSTIEL BASIC MED SCI RES CTR,WALTHAM,MA 02254
关键词
ANESTHETIC PROTEIN INTERACTIONS; WATER POLARIZATION; CARBOXYL GROUP PAIRING; ALLOSTERY;
D O I
10.1073/pnas.91.26.12388
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Crystallographic analysis at 2-Angstrom resolution of the selective binding of dihalogenated methane, ethane, and ethylene compounds in the cavity on the cubic insulin dimer axis provides a model for anesthetic-protein interactions. At pH 6-11, 1,2-dichloroethane binds isomorphically in the right-handed cis-conformation, displacing four water molecules from the invariant cavity. Lowering the pH to 5.7 in 1 M Na2SO4 without dihaloalkanes induces a cooperative structural transition in which the dyad cavities between B13 glutamate pairs are constricted, and SO42- ions are bound by rearranged triads of B1 NH3+ groups. In the presence of dichloroethane at pH 5-5.5, the equilibrium is shifted to a mixture of the ligand-bound and ligand-excluding cavity structures, with half-occupancy of the sulfate sites, exemplifying how a volatile anesthetic can act as an allosteric effector. Measurements at pH 9 of the occupancies of structurally similar dihaloalkanes demonstrate a high degree of binding selectivity. Induced polarization of the ligand and bound water by the charge distribution in the binding cavity apparently provides the selective electrostatic interactions that discriminate between dihaloalkanes of comparable size and polarity.
引用
收藏
页码:12388 / 12392
页数:5
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