29ZZ

Human smooth muscle myosin motor domain co-crystallized with the S(-)2501 inhibitor, MgADP-VO4 form.

This is a non-PDB format compatible entry.

Summary for 29ZZ

• Entry DOI: 10.2210/pdb29zz/pdb
• Related: 29ZY
• Descriptor: Myosin-11, VANADATE ION, ADENOSINE-5'-DIPHOSPHATE, ... (9 entities in total)
• Functional Keywords: smooth muscle, myosin ii, muscle contraction, renal infarction, cardiac infarction, motor modulator, motor domain, motor protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 91900.96

Authors

Kikuti, C.M.,Canon, L.,Heidsieck, L.,Houdusse, A. (deposition date: 2026-04-16, release date: 2026-10-14, Last modification date: 2026-10-28)

Primary citation

Penzes, M.,Winternitz, M.,Horvath, A.I.,Mastitskaya, S.,Awan, U.,Szimler, T.,Glaser, C.,Kikuti, C.,Juille, M.,Heidsieck, L.,Rauscher, A.A.,Balint, T.,Nagy, D.,Radovits, T.,Sayour, A.A.,Gibson, C.M.,Houdusse, A.,Gyimesi, M.,Malnasi-Csizmadia, A.
Capillary-selective vasodilation through myosin inhibition halts ischaemic cascades.
Nature, 2026

PubMed Abstract: In acute myocardial infarction and acute kidney injury, capillary no-reflow denotes that capillary blood flow is still blocked despite successful arterial reperfusion. This is associated with substantially increased mortality and reinfarction risk; nevertheless, no targeted therapy exists so far. Because capillary no-reflow is driven by smooth muscle myosin-mediated hypercontraction of capillary pericytes, we developed R(+)2501, a myosin-specific and capillary-selective vasodilator. In reperfused animal models of acute myocardial infarction and acute kidney injury, direct in vivo imaging showed that R(+)2501 rapidly restored capillary flow, an effect sustained even after rapid drug clearance. Ex vivo experiments confirmed reversal of pericyte constriction directly. Restoration of capillary blood flow, together with clearance of trapped neutrophils, linked resolution of capillary no-reflow to attenuation of an early driver of reperfusion injury. R(+)2501 enhanced capillary perfusion while preserving coronary autoregulation and systemic haemodynamics, and markedly improved survival during acute reperfusion. We further found that acute myocardial infarction induced renal capillary no-reflow, which was reversed by R(+)2501, suggesting that capillary no-reflow contributes to the pathophysiology of cardiorenal syndrome type I. These findings establish pericyte-targeted smooth muscle myosin inhibition as a therapeutic strategy to restore microvascular perfusion and halt the ischaemic cascade across organs, while defining a specific physiological role for capillaries and pericytes in circulatory regulation.

PubMed: 42875490
DOI: 10.1038/s41586-026-11171-6

Experimental method

X-RAY DIFFRACTION (2.3 Å)