1qhc
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(New page: 200px<br /><applet load="1qhc" size="450" color="white" frame="true" align="right" spinBox="true" caption="1qhc, resolution 1.70Å" /> '''CRYSTAL STRUCTURE OF...)
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Revision as of 22:34, 20 November 2007
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CRYSTAL STRUCTURE OF RIBONUCLEASE A IN COMPLEX WITH 5'-PHOSPHO-2'-DEOXYURIDINE-3'-PYROPHOSPHATE ADENOSINE-3'-PHOSPHATE
Overview
The crystal structure of ribonuclease A (RNase A) in complex with, pdUppA-3'-p [5'-phospho-2'-deoxyuridine-3'-pyrophosphate (P'-->5'), adenosine 3'-phosphate] has been determined at 1.7 A resolution. This, dinucleotide is the most potent low molecular weight inhibitor of RNase A, reported to date (K(i) = 27 nM) and is also effective against two major, nonpancreatic RNases: eosinophil-derived neurotoxin and RNase-4; in all, cases, tight binding in large part derives from the unusual, 3',5'-pyrophosphate internucleotide linkage [Russo, N., and Shapiro, R., (1999) J. Biol. Chem. 274, 14902-14908]. The design of pdUppA-3'-p was, based on the crystal structure of RNase A complexed with, 5'-diphosphoadenosine 3'-phosphate (ppA-3'-p) [Leonidas, D. D., Shapiro, R., Irons, L. I., Russo, N., and Acharya, K. R. (1997) Biochemistry 36, 5578-5588]. The adenosine of pdUppA-3'-p adopts an atypical syn, conformation not observed for standard adenosine nucleotides bound to, RNase A. This conformation, which allows extensive interactions with Asn, 67, Gln 69, Asn 71, and His 119, is associated with the placement of the, 5'-beta-phosphate of the adenylate, rather than alpha-phosphate, at the, site where substrate phosphodiester bond cleavage occurs. The contacts of, the deoxyuridine 5'-phosphate portion of pdUppA-3'-p appear to be, responsible for the 9-fold increased affinity of this compound as compared, to ppA-3'-p: the uracil base binds to Thr 45 in the same manner as, previous pyrimidine inhibitors, and the terminal 5'-phosphate is, positioned to form medium-range Coulombic interactions with Lys 66. The, full potential benefit of these added interactions is not realized because, of compensatory losses of hydrogen bonds of Lys 7 and Gln 11 with the, terminal 3'-phosphate and the adenylate 5'-alpha-phosphate, which were not, predicted by modeling. The results reported here have important, implications for the design of improved inhibitors of RNase A and for the, development of therapeutic agents to control the activities of RNase, homologues such as eosinophil-derived neurotoxin and angiogenin that have, roles in human pathologies.
About this Structure
1QHC is a Single protein structure of sequence from Bos taurus with PUA as ligand. Active as Pancreatic ribonuclease, with EC number 3.1.27.5 Full crystallographic information is available from OCA.
Reference
Toward rational design of ribonuclease inhibitors: high-resolution crystal structure of a ribonuclease A complex with a potent 3',5'-pyrophosphate-linked dinucleotide inhibitor., Leonidas DD, Shapiro R, Irons LI, Russo N, Acharya KR, Biochemistry. 1999 Aug 10;38(32):10287-97. PMID:10441122
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