Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-EM structures of wild-type and E138K/M184I mutant HIV-1 RT/DNA complexed with inhibitors doravirine and rilpivirine.
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 119, Issue 30, Page e2203660119, Year 2022
Publish date	Jul 26, 2022
Authors	Abhimanyu K Singh / Brent De Wijngaert / Marc Bijnens / Kris Uyttersprot / Hoai Nguyen / Sergio E Martinez / Dominique Schols / Piet Herdewijn / Christophe Pannecouque / Eddy Arnold / Kalyan Das /
PubMed Abstract	Structures trapping a variety of functional and conformational states of HIV-1 reverse transcriptase (RT) have been determined by X-ray crystallography. These structures have played important roles ...Structures trapping a variety of functional and conformational states of HIV-1 reverse transcriptase (RT) have been determined by X-ray crystallography. These structures have played important roles in explaining the mechanisms of catalysis, inhibition, and drug resistance and in driving drug design. However, structures of several desired complexes of RT could not be obtained even after many crystallization or crystal soaking experiments. The ternary complexes of doravirine and rilpivirine with RT/DNA are such examples. Structural study of HIV-1 RT by single-particle cryo-electron microscopy (cryo-EM) has been challenging due to the enzyme's relatively smaller size and higher flexibility. We optimized a protocol for rapid structure determination of RT complexes by cryo-EM and determined six structures of wild-type and E138K/M184I mutant RT/DNA in complexes with the nonnucleoside inhibitors rilpivirine, doravirine, and nevirapine. RT/DNA/rilpivirine and RT/DNA/doravirine complexes have structural differences between them and differ from the typical conformation of nonnucleoside RT inhibitor (NNRTI)-bound RT/double-stranded DNA (dsDNA), RT/RNA-DNA, and RT/dsRNA complexes; the primer grip in RT/DNA/doravirine and the YMDD motif in RT/DNA/rilpivirine have large shifts. The DNA primer 3'-end in the doravirine-bound structure is positioned at the active site, but the complex is in a nonproductive state. In the mutant RT/DNA/rilpivirine structure, I184 is stacked with the DNA such that their relative positioning can influence rilpivirine in the pocket. Simultaneously, E138K mutation opens the NNRTI-binding pocket entrance, potentially contributing to a faster rate of rilpivirine dissociation by E138K/M184I mutant RT, as reported by an earlier kinetic study. These structural differences have implications for understanding molecular mechanisms of drug resistance and for drug design.
External links	Proc Natl Acad Sci U S A / PubMed:35858448 / PubMed Central
Methods	EM (single particle)
Resolution	3.32 - 3.65 Å
Structure data	14457 7z24 EMDB-14457, PDB-7z24: Cryo-EM structure of HIV-1 reverse transcriptase with a DNA aptamer in complex with nevirapine Method: EM (single particle) / Resolution: 3.32 Å 14458 7z29 EMDB-14458, PDB-7z29: Cryo-EM structure of NNRTI resistant M184I/E138K mutant HIV-1 reverse transcriptase with a DNA aptamer in complex with nevirapine Method: EM (single particle) / Resolution: 3.38 Å 14462 7z2d EMDB-14462, PDB-7z2d: Cryo-EM structure of HIV-1 reverse transcriptase with a DNA aptamer in complex with rilpivirine Method: EM (single particle) / Resolution: 3.38 Å 14463 7z2e EMDB-14463, PDB-7z2e: Cryo-EM structure of NNRTI resistant M184I/E138K mutant HIV-1 reverse transcriptase with a DNA aptamer in complex with rilpivirine Method: EM (single particle) / Resolution: 3.45 Å 14465 7z2g EMDB-14465, PDB-7z2g: Cryo-EM structure of HIV-1 reverse transcriptase with a DNA aptamer in complex with doravirine Method: EM (single particle) / Resolution: 3.65 Å 14466 7z2h EMDB-14466, PDB-7z2h: Cryo-EM structure of NNRTI resistant M184I/E138K mutant HIV-1 reverse transcriptase with a DNA aptamer in complex with doravirine Method: EM (single particle) / Resolution: 3.58 Å
Chemicals	ChemComp-NVP: 11-CYCLOPROPYL-5,11-DIHYDRO-4-METHYL-6H-DIPYRIDO[3,2-B:2',3'-E][1,4]DIAZEPIN-6-ONE / medication, antiretroviralYM ChemComp-T27: 4-{[4-({4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyrimidin-2-yl]amino}benzonitrile / medication, inhibitorYM ChemComp-2KW: 3-chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl}oxy)benzonitrile / medication, inhibitor*YM
Source	human immunodeficiency virus type 1 bh10 synthetic construct (others)
Keywords	TRANSFERASE / Reverse transcriptase / RT-aptamer complex / NON-NUCLEOSIDE INHIBITOR / P51 / P66 / Reverse transcriptase mutant / NNRTI resistance / NNRTI