tailieunhanh - Báo cáo khoa học: The binding of IMP to Ribonuclease A

The binding of inosine 5¢ phosphate (IMP) to ribonuclease A has been studied by kinetic and X-ray crystallographic experiments at high ( A ˚ ) resolution. IMP is a competitive inhibitor of the enzyme with respect to Cp and binds to the catalytic cleft by anchoring three IMP molecules in a novel binding mode. | iFEBS Journal The binding of IMP to Ribonuclease A George N. Hatzopoulos1 Demetres D. Leonidas1 Rozina Kardakaris1 Joze Kobe2 and Nikos G. Oikonomakos1 3 1 Institute of Organic PharmaceuticalChemistry The NationalHellenic Research Foundation Athens Greece 2 NationalInstitute of Chemistry Laboratory for Organic Synthesis and MedicinalChemistry Ljubljana Slovenia 3 Institute of BiologicalResearch Biotechnology The NationalHellenic Research Foundation Athens Greece Keywords ribonuclease A X-ray crystallography IMP structure assisted inhibitor design Correspondence D. D. Leonidas Institute of Organic and PharmaceuticalChemistry The National Hellenic Research Foundation 48 Vas. Constantinou Avenue 11635 Athens Greece Fax 30 210 7273831 Tel 30 210 7273841 E-mail ddl@ Received 1 April 2005 revised 13 June 2005 accepted 15 June 2005 doi The binding of inosine 5 phosphate IMP to ribonuclease A has been studied by kinetic and X-ray crystallographic experiments at high A resolution. IMP is a competitive inhibitor of the enzyme with respect to C p and binds to the catalytic cleft by anchoring three IMP molecules in a novel binding mode. The three IMP molecules are connected to each other by hydrogen bond and van der Waals interactions and collectively occupy the B1R1P1B2P0P-1 region of the ribonucleolytic active site. One of the IMP molecules binds with its nucleobase in the outskirts of the B2 subsite and interacts with Glu111 while its phosphoryl group binds in P1. Another IMP molecule binds by following the retro-binding mode previously observed only for guanosines with its nucleobase at B1 and the phosphoryl group in P-1. The third IMP molecule binds in a novel mode towards the C-terminus. The RNase A-IMP complex provides structural evidence for the functional components of subsite P-1 while it further supports the role inferred by other studies to Asn71 as the primary structural determinant for the adenine specificity of the B2 .

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