A STRUCTURAL COMPARISON OF 21-INHIBITOR COMPLEXES OF THE ASPARTIC PROTEINASE FROM ENDOTHIA-PARASITICA

被引:40
作者
BAILEY, D [1 ]
COOPER, JB [1 ]
机构
[1] UNIV LONDON BIRKBECK COLL,DEPT CRYSTALLOG,LONDON WC1E 7HX,ENGLAND
关键词
ASPARTIC PROTEINASE; INHIBITOR COMPLEXES; TRANSITION-STATE ANALOGS;
D O I
10.1002/pro.5560031126
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
The aspartic proteinases are an important family of enzymes associated with several pathological conditions such as hypertension (renin), gastric ulcers (pepsin), neoplastic disease (cathepsins D and E), and AIDS (HIV proteinase). Studies of inhibitor binding are therefore of great importance for design of novel inhibitors for potential therapeutic applications. Numerous X-ray analyses have shown that transition-state isostere inhibitors of aspartic proteinases bind in similar extended conformations in the active-site cleft of the target enzyme. Upon comparison of 21 endothiapepsin inhibitor complexes, the hydrogen bond lengths were found to be shortest where the isostere (P-1-P-1') interacts with the enzyme's catalytic aspartate pair. Hydrogen bonds with good geometry also occur at P-2', and more so at P-3, where a conserved water molecule is involved in the interactions. Weaker interactions also occur at P-2, where the side-chain conformations of the inhibitors appear to be more variable than at the more tightly held positions. At P-2 and, to a lesser extent, P-3, the side-chain conformations depend intriguingly on interactions with spatially adjacent inhibitor side chains, namely P-1' and P-1, respectively. The tight binding at P-1-P-1', P-3, and P-2' is also reflected in the larger number of van der Waals contacts and the large decreases in solvent-accessible area at these positions, as well as their low temperature factors. Our analysis substantiates earlier proposals for the locations of protons in the transition-state complex. Aspartate 32 is probably ionized in the complexes, its charge being stabilized by 1, or sometimes 2, hydrogen bonds from the transition-state analogues at P-1. The detailed comparison also indicates that the P-1 and P-2 residues of substrate in the ES complex may be strained by the extensive binding interactions at P-3, P-1', and P-2' in a manner that would facilitate hydrolysis of the scissile peptide bond.
引用
收藏
页码:2129 / 2143
页数:15
相关论文
共 41 条
  • [11] COOPER JB, 1988, ROYAL SOC SPECIAL PU, V65, P308
  • [12] THE STRUCTURE AND FUNCTION OF THE ASPARTIC PROTEINASES
    DAVIES, DR
    [J]. ANNUAL REVIEW OF BIOPHYSICS AND BIOPHYSICAL CHEMISTRY, 1990, 19 : 189 - 215
  • [13] X-RAY-ANALYSIS AT 2-CENTER-DOT-0 ANGSTROM RESOLUTION OF MOUSE SUBMAXILLARY RENIN COMPLEXED WITH A DECAPEPTIDE INHIBITOR CH-66, BASED ON THE 4-16 FRAGMENT OF RAT ANGIOTENSINOGEN
    DEALWIS, CG
    FRAZAO, C
    BADASSO, M
    COOPER, JB
    TICKLE, IJ
    DRIESSEN, H
    BLUNDELL, TL
    MURAKAMI, K
    MIYAZAKI, H
    SUEIRASDIAZ, J
    JONES, DM
    SZELKE, M
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1994, 236 (01) : 342 - 360
  • [14] X-RAY ANALYSES OF PEPTIDE-INHIBITOR COMPLEXES DEFINE THE STRUCTURAL BASIS OF SPECIFICITY FOR HUMAN AND MOUSE RENINS
    DHANARAJ, V
    DEALWIS, CG
    FRAZAO, C
    BADASSO, M
    SIBANDA, BL
    TICKLE, IJ
    COOPER, JB
    DRIESSEN, HPC
    NEWMAN, M
    AGUILAR, C
    WOOD, SP
    BLUNDELL, TL
    HOBART, PM
    GEOGHEGAN, KF
    AMMIRATI, MJ
    DANLEY, DE
    OCONNOR, BA
    HOOVER, DJ
    [J]. NATURE, 1992, 357 (6378) : 466 - 472
  • [15] HIGH-RESOLUTION X-RAY ANALYSES OF RENIN INHIBITOR-ASPARTIC PROTEINASE COMPLEXES
    FOUNDLING, SI
    COOPER, J
    WATSON, FE
    CLEASBY, A
    PEARL, LH
    SIBANDA, BL
    HEMMINGS, A
    WOOD, SP
    BLUNDELL, TL
    VALLER, MJ
    NOREY, CG
    KAY, J
    BOGER, J
    DUNN, BM
    LECKIE, BJ
    JONES, DM
    ATRASH, B
    HALLETT, A
    SZELKE, M
    [J]. NATURE, 1987, 327 (6120) : 349 - 352
  • [16] FLUORO KETONE INHIBITORS OF HYDROLYTIC ENZYMES
    GELB, MH
    SVAREN, JP
    ABELES, RH
    [J]. BIOCHEMISTRY, 1985, 24 (08) : 1813 - 1817
  • [17] RESTRAINED STRUCTURE-FACTOR LEAST-SQUARES REFINEMENT OF PROTEIN STRUCTURES USING A VECTOR PROCESSING COMPUTER
    HANEEF, I
    MOSS, DS
    STANFORD, MJ
    BORKAKOTI, N
    [J]. ACTA CRYSTALLOGRAPHICA SECTION A, 1985, 41 (SEP): : 426 - 433
  • [18] CONFORMATIONAL FLEXIBILITY IN THE ACTIVE-SITES OF ASPARTYL PROTEINASES REVEALED BY A PEPSTATIN FRAGMENT BINDING TO PENICILLOPEPSIN
    JAMES, MNG
    SIELECKI, A
    SALITURO, F
    RICH, DH
    HOFMANN, T
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1982, 79 (20): : 6137 - 6141
  • [19] STRUCTURE AND REFINEMENT OF PENICILLOPEPSIN AT 1.8-A RESOLUTION
    JAMES, MNG
    SIELECKI, AR
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1983, 163 (02) : 299 - 361
  • [20] CRYSTALLOGRAPHIC ANALYSIS OF TRANSITION-STATE MIMICS BOUND TO PENICILLOPEPSIN - DIFLUOROSTATINE-CONTAINING AND DIFLUOROSTATONE-CONTAINING PEPTIDES
    JAMES, MNG
    SIELECKI, AR
    HAYAKAWA, K
    GELB, MH
    [J]. BIOCHEMISTRY, 1992, 31 (15) : 3872 - 3886