6LKD

in meso full-length rat KMO in complex with a pyrazoyl benzoic acid inhibitor

Summary for 6LKD

• Entry DOI: 10.2210/pdb6lkd/pdb
• Descriptor: Kynurenine 3-monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE, 5-[5-(4-chloranyl-3-fluoranyl-phenyl)-4-methyl-pyrazol-1-yl]-2-phenylmethoxy-benzoic acid, ... (6 entities in total)
• Functional Keywords: single pass transmembrane, kmo, hydroxygenase, flavoprotein, membrane protein
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 2
• Total formula weight: 115546.32

Authors

Mimasu, S.,Yamagishi, H.,Kiyohara, M.,Kakefuda, K.,Okuda, T. (deposition date: 2019-12-19, release date: 2020-12-23, Last modification date: 2023-11-22)

Primary citation

Mimasu, S.,Yamagishi, H.,Kubo, S.,Kiyohara, M.,Matsuda, T.,Yahata, T.,Thomson, H.A.,Hupp, C.D.,Liu, J.,Okuda, T.,Kakefuda, K.
Full-length in meso structure and mechanism of rat kynurenine 3-monooxygenase inhibition.
Commun Biol, 4:159-159, 2021

PubMed Abstract: The structural mechanisms of single-pass transmembrane enzymes remain elusive. Kynurenine 3-monooxygenase (KMO) is a mitochondrial protein involved in the eukaryotic tryptophan catabolic pathway and is linked to various diseases. Here, we report the mammalian full-length structure of KMO in its membrane-embedded form, complexed with compound 3 (identified internally) and compound 4 (identified via DNA-encoded chemical library screening) at 3.0 Å resolution. Despite predictions suggesting that KMO has two transmembrane domains, we show that KMO is actually a single-pass transmembrane protein, with the other transmembrane domain lying laterally along the membrane, where it forms part of the ligand-binding pocket. Further exploration of compound 3 led to identification of the brain-penetrant compound, 5. We show that KMO is dimeric, and that mutations at the dimeric interface abolish its activity. These results will provide insight for the drug discovery of additional blood-brain-barrier molecules, and help illuminate the complex biology behind single-pass transmembrane enzymes.

PubMed: 33542467
DOI: 10.1038/s42003-021-01666-5

Experimental method

X-RAY DIFFRACTION (3 Å)