1ZOS
Structure of 5'-methylthionadenosine/S-Adenosylhomocysteine nucleosidase from S. pneumoniae with a transition-state inhibitor MT-ImmA
Summary for 1ZOS
| Entry DOI | 10.2210/pdb1zos/pdb |
| Descriptor | 5'-methylthioadenosine / S-adenosylhomocysteine nucleosidase, (3S,4R)-2-(4-AMINO-5H-PYRROLO[3,2-D]PYRIMIDIN-7-YL)-5-[(METHYLSULFANYL)METHYL]PYRROLIDINE-3,4-DIOL (3 entities in total) |
| Functional Keywords | nucleosidase, pneumoniae, transition state, inhibitor, hydrolase |
| Biological source | Streptococcus pneumoniae R6 |
| Total number of polymer chains | 6 |
| Total formula weight | 149983.92 |
| Authors | Shi, W.,Singh, V.,Zhen, R.,Tyler, P.C.,Furneaux, R.H.,Almo, S.C.,Schramm, V.L. (deposition date: 2005-05-13, release date: 2006-04-25, Last modification date: 2023-08-23) |
| Primary citation | Singh, V.,Shi, W.,Almo, S.C.,Evans, G.B.,Furneaux, R.H.,Tyler, P.C.,Painter, G.F.,Lenz, D.H.,Mee, S.,Zheng, R.,Schramm, V.L. Structure and inhibition of a quorum sensing target from Streptococcus pneumoniae. Biochemistry, 45:12929-12941, 2006 Cited by PubMed Abstract: Streptococcus pneumoniae 5'-methylthioadenosine/S-adenosylhomocysteine hydrolase (MTAN) catalyzes the hydrolytic deadenylation of its substrates to form adenine and 5-methylthioribose or S-ribosylhomocysteine (SRH). MTAN is not found in mammals but is involved in bacterial quorum sensing. MTAN gene disruption affects the growth and pathogenicity of bacteria, making it a target for antibiotic design. Kinetic isotope effects and computational studies have established a dissociative S(N)1 transition state for Escherichia coli MTAN, and transition state analogues resembling the transition state are powerful inhibitors of the enzyme [Singh, V., Lee, J. L., Núñez, S., Howell, P. L., and Schramm, V. L. (2005) Biochemistry 44, 11647-11659]. The sequence of MTAN from S. pneumoniae is 40% identical to that of E. coli MTAN, but S. pneumoniae MTAN exhibits remarkably distinct kinetic and inhibitory properties. 5'-Methylthio-Immucillin-A (MT-ImmA) is a transition state analogue resembling an early S(N)1 transition state. It is a weak inhibitor of S. pneumoniae MTAN with a K(i) of 1.0 microM. The X-ray structure of S. pneumoniae MTAN with MT-ImmA indicates a dimer with the methylthio group in a flexible hydrophobic pocket. Replacing the methyl group with phenyl (PhT-ImmA), tolyl (p-TolT-ImmA), or ethyl (EtT-ImmA) groups increases the affinity to give K(i) values of 335, 60, and 40 nM, respectively. DADMe-Immucillins are geometric and electrostatic mimics of a fully dissociated transition state and bind more tightly than Immucillins. MT-DADMe-Immucillin-A inhibits with a K(i) value of 24 nM, and replacing the 5'-methyl group with p-Cl-phenyl (p-Cl-PhT-DADMe-ImmA) gave a K(i) value of 0.36 nM. The inhibitory potential of DADMe-Immucillins relative to the Immucillins supports a fully dissociated transition state structure for S. pneumoniae MTAN. Comparison of active site contacts in the X-ray crystal structures of E. coli and S. pneumoniae MTAN with MT-ImmA would predict equal binding, yet most analogues bind 10(3)-10(4)-fold more tightly to the E. coli enzyme. Catalytic site efficiency is primarily responsible for this difference since k(cat)/K(m) for S. pneumoniae MTAN is decreased 845-fold relative to that of E. coli MTAN. PubMed: 17059210DOI: 10.1021/bi061184i PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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