THE CRYSTAL-STRUCTURE OF A MAJOR SECRETED ASPARTIC PROTEINASE FROM CANDIDA-ALBICANS IN COMPLEXES WITH 2 INHIBITORS

被引:113
作者
CUTFIELD, SM
DODSON, EJ
ANDERSON, BF
MOODY, PCE
MARSHALL, CJ
SULLIVAN, PA
CUTFIELD, JF
机构
[1] UNIV OTAGO,DEPT BIOCHEM,DUNEDIN,NEW ZEALAND
[2] UNIV YORK,DEPT CHEM,YORK YO1 5DD,N YORKSHIRE,ENGLAND
[3] MASSEY UNIV,DEPT CHEM & BIOCHEM,PALMERSTON NORTH,NEW ZEALAND
关键词
ASPARTIC PROTEINASE; CANDIDA ALBICANS; CRYSTAL STRUCTURE; INHIBITORS; ISOENZYME;
D O I
10.1016/S0969-2126(01)00261-1
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: Infections caused by Candida albicans, a common fungal pathogen of humans, are increasing in incidence, necessitating development of new therapeutic drugs. Secreted aspartic proteinase (SAP) activity is considered an important virulence factor in these infections and might offer a suitable target for drug design. Amongst the various SAP isozymes, the SAP2 gene product is the major form expressed in a number of C. albicans strains. Results: The three-dimensional structures of Sap2 complexed with the tight-binding inhibitor A70450 (a synthetic hexapeptide analogue) and with the general aspartic proteinase inhibitor pepstatin A (a microbial natural product) have been determined to 2.1 Angstrom and 3.0 Angstrom resolution, respectively. Although the protein structure retains the main features of a typical aspartic proteinase, it also shows some significant differences, due mainly to several sequence insertions and deletions (as revealed by homology modelling), that alter the shape of the binding cleft. There is also considerable variation in the C-terminal structural domain. Conclusions: The differences in side chains, and in the conformations adopted by the two inhibitors, particularly at their P4, P3 and P'2 positions (using standard notation for protease-inhibitor residues), allows the A70450 structure to complement, more accurately, that of the substrate-binding site of SAP2. Some differences in the binding clefts of other SAP isoenzymes may be deduced from the SAP2 structure.
引用
收藏
页码:1261 / 1271
页数:11
相关论文
共 47 条
  • [1] REVISED 2.3-A STRUCTURE OF PORCINE PEPSIN - EVIDENCE FOR A FLEXIBLE SUBDOMAIN
    ABADZAPATERO, C
    RYDEL, TJ
    ERICKSON, J
    [J]. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 1990, 8 (01) : 62 - 81
  • [2] [Anonymous], 1994, ACTA CRYSTALLOGR D, V50, P760
  • [3] X-RAY-CRYSTALLOGRAPHIC STUDIES OF COMPLEXES OF PEPSTATIN-A AND A STATINE-CONTAINING HUMAN RENIN INHIBITOR WITH ENDOTHIAPEPSIN
    BAILEY, D
    COOPER, JB
    VEERAPANDIAN, B
    BLUNDELL, TL
    ATRASH, B
    JONES, DM
    SZELKE, M
    [J]. BIOCHEMICAL JOURNAL, 1993, 289 : 363 - 371
  • [4] A STRUCTURAL COMPARISON OF 21-INHIBITOR COMPLEXES OF THE ASPARTIC PROTEINASE FROM ENDOTHIA-PARASITICA
    BAILEY, D
    COOPER, JB
    [J]. PROTEIN SCIENCE, 1994, 3 (11) : 2129 - 2143
  • [5] CRYSTAL-STRUCTURES OF NATIVE AND INHIBITED FORMS OF HUMAN CATHEPSIN-D - IMPLICATIONS FOR LYSOSOMAL TARGETING AND DRUG DESIGN
    BALDWIN, ET
    BHAT, TN
    GULNIK, S
    HOSUR, MV
    SOWDER, RC
    CACHAU, RE
    COLLINS, J
    SILVA, AM
    ERICKSON, JW
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (14) : 6796 - 6800
  • [6] PROTEIN DATA BANK - COMPUTER-BASED ARCHIVAL FILE FOR MACROMOLECULAR STRUCTURES
    BERNSTEIN, FC
    KOETZLE, TF
    WILLIAMS, GJB
    MEYER, EF
    BRICE, MD
    RODGERS, JR
    KENNARD, O
    SHIMANOUCHI, T
    TASUMI, M
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1977, 112 (03) : 535 - 542
  • [7] ASSESSMENT OF PHASE ACCURACY BY CROSS VALIDATION - THE FREE R-VALUE - METHODS AND APPLICATIONS
    BRUNGER, AT
    [J]. ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1993, 49 : 24 - 36
  • [8] BRUNGER AT, 1992, X PLOR MANUAL VERSIO
  • [9] APPLICATION OF A FLUOROGENIC SUBSTRATE IN THE ASSAY OF PROTEOLYTIC ACTIVITY AND IN THE DISCOVERY OF A POTENT INHIBITOR OF CANDIDA-ALBICANS ASPARTIC PROTEINASE
    CAPOBIANCO, JO
    LERNER, CG
    GOLDMAN, RC
    [J]. ANALYTICAL BIOCHEMISTRY, 1992, 204 (01) : 96 - 102
  • [10] STRUCTURE OF A PEPSIN RENIN INHIBITOR COMPLEX REVEALS A NOVEL CRYSTAL PACKING INDUCED BY MINOR CHEMICAL ALTERATIONS IN THE INHIBITOR
    CHEN, LQ
    ERICKSON, JW
    RYDEL, TJ
    PARK, CH
    NEIDHART, D
    LULY, J
    ABADZAPATERO, C
    [J]. ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE CRYSTAL ENGINEERING AND MATERIALS, 1992, 48 : 476 - 488