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Titolo:
STRUCTURES OF NATIVE AND COMPLEXED COMPLEMENT FACTOR-D - IMPLICATIONSOF THE ATYPICAL HIS57 CONFORMATION AND SELF-INHIBITORY LOOP IN THE REGULATION OF SPECIFIC SERINE-PROTEASE ACTIVITY
Autore:
JING H; BABU YS; MOORE D; KILPATRICK JM; LIU XY; VOLANAKIS JE; NARAYANA SVL;
Indirizzi:
UNIV ALABAMA,CTR MACROMOL CRYSTALLOG BIRMINGHAM AL 35294 UNIV ALABAMA,CTR MACROMOL CRYSTALLOG BIRMINGHAM AL 35294 BIOCRYST PHARMACEUT INC BIRMINGHAM AL 35244 UNIV ALABAMA,DIV CLIN IMMUNOL & RHEUMATOL BIRMINGHAM AL 35294
Titolo Testata:
Journal of Molecular Biology
fascicolo: 5, volume: 282, anno: 1998,
pagine: 1061 - 1081
SICI:
0022-2836(1998)282:5<1061:SONACC>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
PORCINE PANCREATIC ELASTASE; RAY CRYSTAL-STRUCTURE; PRO-ARG CHLOROMETHYLKETONE; ACYL-ENZYME INTERMEDIATE; HUMAN-LEUKOCYTE ELASTASE; HUMAN ALPHA-THROMBIN; FREE R-VALUE; ISOCOUMARIN INHIBITORS; SUBSTRATE-SPECIFICITY; STRUCTURE REFINEMENT;
Keywords:
COMPLEMENT FACTOR D; SERINE PROTEASE; DRUG DESIGN; PROTEIN STRUCTURE; X-RAY CRYSTALLOGRAPHY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
79
Recensione:
Indirizzi per estratti:
Citazione:
H. Jing et al., "STRUCTURES OF NATIVE AND COMPLEXED COMPLEMENT FACTOR-D - IMPLICATIONSOF THE ATYPICAL HIS57 CONFORMATION AND SELF-INHIBITORY LOOP IN THE REGULATION OF SPECIFIC SERINE-PROTEASE ACTIVITY", Journal of Molecular Biology, 282(5), 1998, pp. 1061-1081

Abstract

Factor D is a serine protease essential for the activation of the alternative pathway of complement; The structures of native factor D and a complex formed with isatoic anhydride inhibitor were determined at resolution of 2.3 and 1.5 Angstrom, respectively, in an isomorphous monoclinic crystal form containing one molecule per asymmetric unit. The native structure was compared with structures determined previously ina triclinic cell containing two molecules with different active site conformations. The current structure shows greater similarity with molecule B in the triclinic cell, suggesting that this may be the dominant factor D conformation in solution. The major conformational differences with molecule A in the triclinic cell are located in four regions,three of which are close to the active site and include some of the residues shown to be critical for factor D catalytic activity. The conformational flexibility associated with these regions is proposed to provide a structural basis for the previously proposed substrate-inducedreversible conformational changes in factor D. The high-resolution structure of the factor D/isatoic anhydride complex reveals the binding mode of the mechanism-based inhibitor. The higher specificity towards factor D over trypsin and thrombin is based on hydrophobic interactions between the inhibitor benzyl ring and the aliphatic side-chain of Arg218 that is salt bridged with Asp189 at the bottom of the primary specificity (S1) pocket. Comparison of factor D structural variants with other serine protease structures revealed the presence of a unique ''self-inhibitory loop''. This loop (214-218) dictates the resting-state conformation of factor D by (1) preventing His57 from adopting active tautomer conformation, (2) preventing the P1 to P3 residues of the substrate from forming anti-parallel beta-sheets with the non-specific substrate binding loop, and (3) blocking the accessibility of Asp189 to the positively charged P1 residue of the substrate. The conformationalswitch from resting-state to active-state can only be induced by the single macromolecular substrate, C3b-bound factor B. This self-inhibitory mechanism is highly correlated with the unique functional properties of factor D, which include high specificity toward factor B, low esterolytic activity toward synthetic substrates, and absence of regulation by zymogen and serpin-like or other natural inhibitors in blood. (C) 1998 Academic Press.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/10/20 alle ore 16:03:14