scholarly journals Structural Basis of Substrate Recognition in ThiopurineS-Methyltransferase†‡

Biochemistry ◽  
2008 ◽  
Vol 47 (23) ◽  
pp. 6216-6225 ◽  
Author(s):  
Yi Peng ◽  
Qiping Feng ◽  
Dennis Wilk ◽  
Araba A. Adjei ◽  
Oreste E. Salavaggione ◽  
...  
Keyword(s):  
Substrate Recognition ◽  
Structural Basis

scholarly journals Structural Basis and Sequence Rules for Substrate Recognition by Tankyrase Explain the Basis for Cherubism Disease

Cell ◽  
2012 ◽  
Vol 148 (1-2) ◽  
pp. 376
Author(s):  
Sebastian Guettler ◽  
Jose LaRose ◽  
Evangelia Petsalaki ◽  
Gerald Gish ◽  
Andy Scotter ◽  
...  
Keyword(s):  
Substrate Recognition ◽  
Structural Basis ◽  
Sequence Rules

scholarly journals Structural basis of HMCES interactions with DNA reveals multivalent substrate recognition

2019 ◽  
Author(s):  
Levon Halabelian ◽  
Mani Ravichandran ◽  
Yanjun Li ◽  
Hong Zheng ◽  
L. Aravind ◽  
...  
Keyword(s):  
Dna Damage ◽  
Crystal Structures ◽  
Genome Instability ◽  
Substrate Recognition ◽  
Catalytic Triad ◽  
Structural Basis ◽  
Replication Forks ◽  
Abasic Sites ◽  
Stalled Replication Forks ◽  
Gapped Dna

ABSTRACTHMCES can covalently crosslink to abasic sites in single-stranded DNA at stalled replication forks to prevent genome instability. Here, we report crystal structures of the HMCES SRAP domain in complex with DNA-damage substrates, revealing interactions with both single-stranded and duplex segments of 3’ overhang DNA. HMCES may also bind gapped DNA and 5’ overhang structures to align single stranded abasic sites for crosslinking to the conserved Cys2 of its catalytic triad.

scholarly journals Structural basis of substrate recognition and translocation by human ABCD1

2021 ◽  
Author(s):  
Zhipeng Chen ◽  
Da Xu ◽  
Liang Wang ◽  
Cong-Zhao Zhou ◽  
Wen-Tao Hou ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Substrate Recognition ◽  
Acyl Chain ◽  
Chain Fatty Acid ◽  
Structural Basis ◽  
Long Chain Fatty Acid ◽  
Lateral Entry ◽  
Binding Domains ◽  
Acyl Chains ◽  
Functional States

Human ATP-binding cassette (ABC) subfamily D transporter ABCD1 can transport CoA esters of saturated/monounsaturated long/very long chain fatty acid into the peroxisome for β-oxidation. Dysfunction of human ABCD1 causes X-linked adrenoleukodystrophy, which is a severe progressive genetic disorder affecting the nervous system. Nevertheless, the mechanistic details of substrate recognition and translocation by ABCD1 remains obscure. Here, we present three cryo-EM structures of human ABCD1 in distinct functional states. In the apo-form structure of 3.53 Å resolution, ABCD1 exhibits an inward-facing conformation, allowing the lateral entry of substrate from the lipid bilayer. In the 3.59 Å structure of substrate-bound ABCD1, two molecules of C22:0-CoA, the physiological substrate of ABCD1, is symmetrically bound in two transmembrane domains (TMDs). Each C22:0-CoA adopts a L-shape, with its CoA portion and acyl chain components bound to two TMDs respectively, resembling a pair of strings that pull the TMDs closer, resultantly generating a narrower outward-facing conformation. In the 2.79 Å ATP-bound ABCD1 structure, the two nucleotide-binding domains dimerize, leading to an outward-facing conformation, which opens the translocation cavity exit towards the peroxisome matrix side and releases the substrates. Our study provides a molecular basis to understand the mechanism of ABCD1-mediated substrate recognition and translocation, and suggests a unique binding pattern for amphipathic molecules with long acyl chains.

Structural basis of substrate recognition and translocation by human ABCA4

2021 ◽  
Author(s):  
Tian Xie ◽  
Zike Zhang ◽  
Bowen Du ◽  
Qi Fang ◽  
Xin Gong
Keyword(s):  
Substrate Recognition ◽  
Bound State ◽  
Lipid Transport ◽  
Structural Basis ◽  
Lateral Entry ◽  
Closed Conformation ◽  
Hereditary Disorders ◽  
Extrusion Mechanism ◽  
Functional States ◽  
Lipid Compounds

AbstractHuman ATP-binding cassette (ABC) subfamily A (ABCA) transporters mediate the transport of various lipid compounds across the membrane. Mutations in human ABCA transporters have been described to cause severe hereditary disorders associated with impaired lipid transport. However, little is known about the mechanistic details of substrate recognition and translocation by ABCA transporters. Here, we present three cryo-EM structures of human ABCA4, a retinal-specific ABCA transporter, in distinct functional states at resolutions of 3.3-3.4 Å. In the nucleotide-free state, the two transmembrane domains (TMDs) exhibited a lateral-opening conformation, allowing the lateral entry of substrate from the lipid bilayer. N-retinylidene-phosphatidylethanolamine (NRPE), the physiological lipid substrate of ABCA4, is sandwiched between the two TMDs in the luminal leaflet and is further stabilized by an extended loop from extracellular domain 1. In the ATP-bound state, the two TMDs displayed an unprecedented closed conformation, which precludes the substrate binding. Our study provides a molecular basis to understand the mechanism of ABCA4-mediated NRPE recognition and translocation, and suggests a common ‘lateral access and extrusion’ mechanism for ABCA-mediated lipid transport.

Structural basis of cofactor-mediated stabilization and substrate recognition of the α-tubulin acetyltransferase αTAT1

2015 ◽  
Vol 467 (1) ◽  
pp. 103-113 ◽  
Author(s):  
Satoru Yuzawa ◽  
Sachiko Kamakura ◽  
Junya Hayase ◽  
Hideki Sumimoto
Keyword(s):  
Catalytic Domain ◽  
Substrate Recognition ◽  
Structural Basis ◽  
Stable Complex ◽  
Amino Acid Residues ◽  
Substrate Selection ◽  
Post Translational Modification ◽  
Acetyl Group

The functions of microtubules are controlled in part by tubulin post-translational modification including acetylation of Lys40 in α-tubulin. αTAT1 (α-tubulin acetyltransferase 1), an enzyme evolutionarily conserved among eukaryotes, has recently been identified as the major α-tubulin Lys40 acetyltransferase, in which AcCoA (acetyl-CoA) serves as an acetyl group donor. The regulation and substrate recognition of this enzyme, however, have not been fully understood. In the present study, we show that AcCoA and CoA each form a stable complex with human αTAT1 to maintain the protein integrity both in vivo and in vitro. The invariant residues Arg132 and Ser160 in αTAT1 participate in the stable interaction not only with AcCoA but also with CoA, which is supported by analysis of the present crystal structures of the αTAT1 catalytic domain in complex with CoA. Alanine substitution for Arg132 or Ser160 leads to a drastic misfolding of the isolated αTAT1 catalytic domain in the absence of CoA and AcCoA but not in the presence of excess amounts of either cofactor. A mutant αTAT1 carrying the R132A or S160A substitution is degraded much faster than the wild-type protein when expressed in mammalian Madin–Darby canine kidney cells. Furthermore, alanine-scanning experiments using Lys40-containing peptides reveal that α-tubulin Ser38 is crucial for substrate recognition of αTAT1, whereas Asp39, Ile42, the glycine stretch (amino acid residues 43–45) and Asp46 are also involved. The requirement for substrate selection is totally different from that in various histone acetyltransferases, which appears to be consistent with the inability of αTAT1 to acetylate histones.

scholarly journals Structural basis for chiral substrate recognition by two 2,3-butanediol dehydrogenases

FEBS Letters ◽  
2009 ◽  
Vol 584 (1) ◽  
pp. 219-223 ◽  
Author(s):  
Masato Otagiri ◽  
Sadaharu Ui ◽  
Yuhsuke Takusagawa ◽  
Takashi Ohtsuki ◽  
Genji Kurisu ◽  
...  
Keyword(s):  
Substrate Recognition ◽  
Structural Basis

scholarly journals Structural basis for acceptor-substrate recognition of UDP-glucose: anthocyanidin 3-O-glucosyltransferase fromClitoria ternatea

2015 ◽  
Vol 24 (3) ◽  
pp. 395-407 ◽  
Author(s):  
Takeshi Hiromoto ◽  
Eijiro Honjo ◽  
Naonobu Noda ◽  
Taro Tamada ◽  
Kohei Kazuma ◽  
...  
Keyword(s):  
Substrate Recognition ◽  
Structural Basis ◽  
Acceptor Substrate
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