Crystallographic studies of isosteric NAD analogues bound to alcohol dehydrogenase: Specificity and substrate binding in two ternary complexes Journal Article
| Authors: | Li, H.; Hallows, W. H.; Punzi, J. S.; Pankiewicz, K. W.; Watanabe, K. A.; Goldstein, B. M. |
| Article Title: | Crystallographic studies of isosteric NAD analogues bound to alcohol dehydrogenase: Specificity and substrate binding in two ternary complexes |
| Abstract: | CNAD (5-β-D-ribofuranosylnicotinamide adenine dinucleotide) is an isosteric C-glycosidic analogue of NAD(H) containing a neutral pyridine ring. CPAD (5-β-D-ribofuranosylpicolinamide adenine dinucleotide) is a closely related pyridine-containing analogue with the pyridine nitrogen on the opposite side of the ring. CNAD is a potent and specific inhibitor of horse liver alcohol dehydrogenase (LADH), binding with a dissociation constant in the nanomolar range. CPAD binds LADH with an affinity comparable to that of NAD. Crystal structures of CNAD and CPAD bound to LADH are presented at 2.4 and 2.7 Å, respectively. The two complexes are isomorphous, crystallizing in the triclinic system with cell dimensions different from those seen in previous ternary LADH complexes. Structures were solved using the molecular replacement method and refined to crystallographic R values of 18% (CNAD) and 17% (CPAD). Both inhibitors bind to the “closed” form of LADH in the normal cofactor-binding cleft. The conformation of LADH-bound CPAD closely mimics that of LADH-bound NAD(H). The data suggest that alcohol substrate binds directly to the catalytic zinc atom. In the CNAD complex, the pyridine nitrogen replaces alcohol as the fourth coordination ligand to the active site zinc atom, while all other polar interactions remain the same as those of bound NAD(H). The zinc-nitrogen ligand explains the high affinity of CNAD for LADH. © 1994, American Chemical Society. All rights reserved. |
| Keywords: | unclassified drug; binding affinity; animal; enzyme inhibition; protein protein interaction; structure activity relation; liver; models, molecular; crystallography, x-ray; binding sites; conformation; protein structure; zinc; structure analysis; enzyme binding; molecular conformation; nad; ethanol; nicotinamide adenine dinucleotide; enzyme active site; horses; alcohol dehydrogenase; molecular mimicry; priority journal; article; equus caballus; support, u.s. gov't, p.h.s.; picolinamide 5 beta riboside adenine dinucleotide |
| Journal Title: | Biochemistry |
| Volume: | 33 |
| Issue: | 39 |
| ISSN: | 0006-2960 |
| Publisher: | American Chemical Society |
| Date Published: | 1994-10-04 |
| Start Page: | 11734 |
| End Page: | 11744 |
| Language: | English |
| DOI: | 10.1021/bi00205a009 |
| PROVIDER: | scopus |
| PUBMED: | 7918390 |
| DOI/URL: | |
| Notes: | Export Date: 14 January 2019 -- Article -- Source: Scopus |
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