title: Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins.
abstract: Ricin A-chain (RTA) and saporin-L1 (SAP) catalyze adenosine depurination of 28S rRNA to inhibit protein synthesis and cause cell death. We present the crystal structures of RTA and SAP in complex with transition state analogue inhibitors. These tight-binding inhibitors mimic the sarcin-ricin recognition loop of 28S rRNA and the dissociative ribocation transition state established for RTA catalysis. RTA and SAP share unique purine-binding geometry with quadruple pi-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the pi-stack provides cationic polarization and enhanced leaving group ability to the susceptible adenine. Common features of these ribosome-inactivating proteins include adenine leaving group activation, a remarkable lack of ribocation stabilization, and conserved glutamates as general bases for activation of the H(2)O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors.forename: Meng-Chiao
authors.initials: MC
authors.lastname: Ho
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Sturm
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D001120:Arginine / Q000737:chemistry; D003460:Crystallization; D008958:Models, Molecular; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry; D054788:Ribosome Inactivating Proteins / Q000737:chemistry*; D054789:Ribosome Inactivating Proteins, Type 1 / Q000737:chemistry*; D012276:Ricin / Q000737:chemistry*; D000076985:Saporins
chemical_list: D011687:Purines; D054789:Ribosome Inactivating Proteins, Type 1; D012276:Ricin; D001120:Arginine; D054788:Ribosome Inactivating Proteins; D000076985:Saporins