5X9D

Crystal structure of homoserine dehydrogenase in complex with L-cysteine and NAD

Summary for 5X9D

• Entry DOI: 10.2210/pdb5x9d/pdb
• Related: 4YDR 5AVO
• Descriptor: Homoserine dehydrogenase, (2R)-3-[[(4S)-3-aminocarbonyl-1-[(2R,3R,4S,5R)-5-[[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxymethyl]-3,4-bis(oxidanyl)oxolan-2-yl]-4H-pyridin-4-yl]sulfanyl]-2-azanyl-propanoic acid, L(+)-TARTARIC ACID, ... (4 entities in total)
• Functional Keywords: oxidoreductase, complex, inhibitor
• Biological source: Sulfolobus tokodaii (strain DSM 16993 / JCM 10545 / NBRC 100140 / 7)
• Total number of polymer chains: 1
• Total formula weight: 34346.17

Authors

Goto, M.,Ogata, K.,Kaneko, R.,Yoshimune, K. (deposition date: 2017-03-06, release date: 2018-05-02, Last modification date: 2024-10-16)

Primary citation

Ogata, K.,Yajima, Y.,Nakamura, S.,Kaneko, R.,Goto, M.,Ohshima, T.,Yoshimune, K.
Inhibition of homoserine dehydrogenase by formation of a cysteine-NAD covalent complex
Sci Rep, 8:5749-5749, 2018

PubMed Abstract: Homoserine dehydrogenase (EC 1.1.1.3, HSD) is an important regulatory enzyme in the aspartate pathway, which mediates synthesis of methionine, threonine and isoleucine from aspartate. Here, HSD from the hyperthermophilic archaeon Sulfolobus tokodaii (StHSD) was found to be inhibited by cysteine, which acted as a competitive inhibitor of homoserine with a Ki of 11 μM and uncompetitive an inhibitor of NAD and NADP with Ki's of 0.55 and 1.2 mM, respectively. Initial velocity and product (NADH) inhibition analyses of homoserine oxidation indicated that StHSD first binds NAD and then homoserine through a sequentially ordered mechanism. This suggests that feedback inhibition of StHSD by cysteine occurs through the formation of an enzyme-NAD-cysteine complex. Structural analysis of StHSD complexed with cysteine and NAD revealed that cysteine situates within the homoserine binding site. The distance between the sulfur atom of cysteine and the C4 atom of the nicotinamide ring was approximately 1.9 Å, close enough to form a covalent bond. The UV absorption-difference spectrum of StHSD with and without cysteine in the presence of NAD, exhibited a peak at 325 nm, which also suggests formation of a covalent bond between cysteine and the nicotinamide ring.

PubMed: 29636528
DOI: 10.1038/s41598-018-24063-1

Experimental method

X-RAY DIFFRACTION (2.1 Å)