Structure-guided engineering ofmeso-diaminopimelate dehydrogenase for enantioselective reductive amination of sterically bulky 2-keto acids

2018 ◽  
Vol 8 (19) ◽  
pp. 4994-5002 ◽  
Author(s):  
Xinkuan Cheng ◽  
Xi Chen ◽  
Jinhui Feng ◽  
Qiaqing Wu ◽  
Dunming Zhu
Keyword(s):  
Reductive Amination ◽  
Substrate Binding ◽  
Binding Pocket ◽  
Substrate Binding Pocket ◽  
Keto Acids

Structure-guided reshaping the substrate-binding pocket of ameso-diaminopimelate dehydrogenase (StDAPDH) led to a mutant W121L/H227I, which catalyzed the enantioselective reductive amination of some sterically bulky 2-keto acids.

scholarly journals Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yufei Han ◽  
Qian Zhuang ◽  
Bo Sun ◽  
Wenping Lv ◽  
Sheng Wang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Biochemical Characterization ◽  
Substrate Binding ◽  
Binding Pocket ◽  
Substrate Binding Pocket ◽  
Transmembrane Segments ◽  
Therapeutic Molecules ◽  
Binding Cavity ◽  
Immune System Regulation ◽  
Mediated Reduction

AbstractSteroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-Δ4 structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A from Proteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ4 reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.

Characterization of the Acyl Substrate Binding Pocket of Acetyl-CoA Synthetase†

Biochemistry ◽  
2006 ◽  
Vol 45 (38) ◽  
pp. 11482-11490 ◽  
Author(s):  
Cheryl Ingram-Smith ◽  
Barrett I. Woods ◽  
Kerry S. Smith
Keyword(s):  
Substrate Binding ◽  
Binding Pocket ◽  
Substrate Binding Pocket ◽  
Acetyl Coa

scholarly journals The Hydrophobic Hinge Region of Rat DNA Polymerase β Is Critical for Substrate Binding Pocket Geometry

2005 ◽  
Vol 280 (31) ◽  
pp. 28388-28393 ◽  
Author(s):  
Daniela Starcevic ◽  
Shibani Dalal ◽  
Joachim Jaeger ◽  
Joann B. Sweasy
Keyword(s):  
Dna Polymerase ◽  
Substrate Binding ◽  
Binding Pocket ◽  
Hinge Region ◽  
Dna Polymerase Β ◽  
Substrate Binding Pocket
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